Ion binding polymers and uses thereof

ABSTRACT

The present invention provides methods and compositions for the treatment of ion imbalances. In particular, the invention provides compositions comprising potassium binding polymers and pharmaceutical compositions thereof. Methods of use of the polymeric and pharmaceutical compositions for therapeutic and/or prophylactic benefits are disclosed herein. Examples of these methods include the treatment of hyperkalemia, such as hyperkalemia caused by renal failure and/or the use of hyperkalemia causing drugs.

CROSS-REFERENCE

This application is a continuation-in-part of U.S. application Ser. No.10/965,274, filed Oct. 13, 2004 now U.S. Pat. No. 7,488,495 which is acontinuation-in-part application of U.S. application Ser. No.10/814,527, filed Mar. 30, 2004; U.S. application Ser. No. 10/814,749,filed Mar. 30, 2004; and U.S. application Ser. No. 10/813,872, filedMar. 30, 2004 which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

Potassium (K⁺) is the most abundant intracellular cation, comprising˜35-40 mEq/kg in humans. See Agarwal, R, et al. (1994) Gastroenterology107: 548-571; Mandal, A K (1997) Med Clin North Am 81: 611-639. Only1.5-2.5% of this is extracellular. Potassium is obtained through thediet, mainly through vegetables, fruits, meats and dairy products, withcertain food such as potatoes, beans, bananas, beef and turkey beingespecially rich in this element. See Hunt, C D and Meacham, S L (2001) JAm Diet Assoc 101: 1058-1060; Hazell, T (1985) World Rev Nutr Diet 46:1-123. In the US, intake is ˜80 mEq/day. About 80% of this intake isabsorbed from the gastrointestinal tract and excreted in the urine, withthe balance excreted in sweat and feces. Thus, potassium homeostasis ismaintained predominantly through the regulation of renal excretion.Where renal excretion of K⁺ is impaired, elevated serum K⁺ levels willoccur. Hyperkalemia is a condition wherein serum potassium is greaterthan about 5.0 mEq/L.

While mild hyperkalemia, defined as serum potassium of about 5.0-6mEq/L, is not normally life threatening, moderate to severe hyperkalemia(with serum potassium greater than about 6.1 mEq/L) can have graveconsequences. Cardiac arrythmias and altered ECG waveforms arediagnostic of hyperkalemia. See Schwartz, M W (1987) Am J Nurs 87:1292-1299. When serum potassium levels increases above about 9 mEq/L,atrioventricular dissociation, ventricular tachycardia, or ventricularfibrillation can occur.

Hyperkalemia is rare in the general population of healthy individuals.However, certain groups definitely exhibit a higher incidence ofhyperkalemia. In patients who are hospitalized, the incidence ofhyperkalemia ranges from about 1-10%, depending on the definition ofhyperkalemia. Patients at the extremes of life, either premature orelderly, are at high risk. The presence of decreased renal function,genitourinary disease, cancer, severe diabetes, and polypharmacy canalso predispose patients to hyperkalemia.

Most of the current treatment options for hyperkalemia are limited touse in hospitals. For example, exchange resins, such as Kayexalate, arenot suitable for outpatient or chronic treatment, due to the large dosesnecessary that leads to very low patient compliance, severe GI sideeffects and significant introduction of sodium (potentially causinghypernatremia and related fluid retention and hypertension). Diureticsthat can remove sodium and potassium from patients via the kidneys areoften limited in their efficacy due to underlying kidney disease andfrequently related diuretic resistance. Diuretics are alsocontraindicated in patients where a drop in blood pressure and volumedepletion are undesired (e.g. CHF patients that in addition to sufferingfrom low blood pressure are often on a combination of drugs such as ACEinhibitors and potassium sparing diuretics such as spironolactone thatcan induce hyperkalemia).

Overall, it would be desirable to obtain higher binding capacitymaterials for the treatment of hyperkalemia, such materials preferablyhaving a greater binding in the physiological pH range for potassium,which are also non-degradable, non-absorbable and have decreased toxiceffects.

SUMMARY OF THE INVENTION

The present invention provides compositions and methods for the removalof potassium ions from the gastro-intestinal tract. In one embodiment,an effective amount of a potassium binding polymer is administered to ananimal subject, such as a human, the polymer being capable of bindingand removing an average of 1.5 mmol or higher of potassium per gm ofpolymer. In another embodiment, the polymer has an average in vitrobinding capacity of greater than about 5 mmol/gm of polymer at a pH ofgreater than about 5.5. In another embodiment, the potassium bindingpolymer further comprises a shell that is physically or chemicallyattached to the polymer.

The potassium binding polymer is preferably a poly-fluoroacrylic acidpolymer, a poly-difluoromaleic acid polymer, poly-sulfonic acid, or acombination thereof. In other embodiments the polymer comprises2-fluoroacrylic acid crosslinked with divinylbenzene, ethylenebisacrylamide, N,N′-bis(vinylsulfonylacetyl)ethylene diamine,1,3-bis(vinylsulfonyl) 2-propanol, vinylsulfone,N,N′-methylenebisacrylamide polyvinyl ether, polyallylether, or acombination thereof. Preferably, the shell comprises of copolymers of avinylamine, ethyleneimine, propyleneimine, allylamine, methallylamine,vinylpyridines, alkyaminoalkyl(meth)acrylates,alkyaminoalkyl(meth)acrylamides, aminomethylstyrene, chitosan, adductsof aliphatic amine or aromatic amine with electrophile such asepichlorhydrine, alkylhalides or epoxides, and wherein the amine isoptionally a quarternized form. Optionally, the shell can be crosslinkedby epoxides, halides, esters, isocyanate, or anhydrides such asepichlorohydrine, alkyl diisocyanates, alkyl dihalides, or diesters.

In a preferred embodiment, the potassium binding polymer is aα-fluoroacrylate polymer crosslinked with divinyl benzene. A preferredcore-shell composition comprises a core of polystyrene sulfonate orα-fluoroacrylate polymer crosslinked with divinyl benzene and a shell ofEudragit RL 100, Eudragit RS 100, a combination thereof, benzylatedpolyethyleneimine, or N-dodecyl polyethyleneimine. Preferably, the coreshell compositions are synthesized by a Wurster fluid bed coatingprocess or a controlled coating precipitation process. Suitablecontrolled coating precipitation process includes solvent coacervationprocess, a pH triggered precipitation process, or temperature triggeredprecipitation process.

The compositions described herein are suitable for therapeutic and/orprophylactic use in the treatment of hyperkalemia. In one embodiment,the potassium binding compositions are used in combination with drugsthat cause potassium retention such as potassium-sparing diuretics,angiotensin-converting enzyme inhibitors (ACEIs), Angiotensin receptorblockers (ARBs), non-steroidal anti-inflammatory drugs, heparin, ortrimethoprim.

A preferred method for removing potassium from an animal subjectcomprises administering a potassium-binding polymer an α-fluoroacrylatepolymer crosslinked with divinyl benzene. In another method, potassiumis removed from a patient with a core-shell composition comprising acore of polystyrene sulfonate or α-fluoroacrylate polymer crosslinkedwith divinyl benzene and a shell of Eudragit RL 100, Eudragit RS 100, acombination thereof, benzylated polyethyleneimine, or N-dodecylpolyethyleneimine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts starting cation concentrations in a meal mimic.

FIG. 2 depicts binding of cations by resins in a meal mimic.

FIG. 3 depicts the original concentrations of cations in the feces oftwo subjects.

FIG. 4 depicts the binding of cations in human fecal extracts to cationexchange resins.

FIG. 5 depicts the membrane preparation for determination of ionpermeability.

FIG. 6 depicts the binding data of different polyethyleneimine coatedbeads for different cations.

FIG. 7 depicts the effect of a Eudragit RL 100 shell on magnesium andpotassium binding.

FIG. 8 depicts binding of magnesium on benzylated polyethyleneiminecoated Dowex (K) beads.

FIG. 9 depicts the stability of Ben(84)-PEI coated Dowex (K) beads underacid conditions representative of the acidic conditions in the stomach.

FIG. 10 depicts potassium and magnesium binding by Dowex beads coatedwith benzylated polyethyleneimine.

FIG. 11 depicts magnesium binding by fluoroacrylic acid beads withbenzylated polyethylene imine shell.

FIG. 12 depicts a setup for determining membrane permeability.

FIG. 13 depicts the permeability of benzylated polyethyleneiminemembrane.

FIG. 14 depicts the permeability and permselectivity of membranescomprising of mixtures of Eudragit RL100 and Eudragit RS 100.

FIG. 15 depicts the effects of bile acids on potassium binding byDowex(Li) coated with polyethyleneimine.

FIG. 16 depicts the effect of pH on α-fluoroacrylate-acrylic acidcopolymer.

FIG. 17 depicts levels of excretion of cations in rats followingadministration of fluoroacrylate polymer and Kayexalate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods, polymeric pharmaceuticalcompositions, and kits for the treatment of animal subjects. The terms“animal subject” and “animal” as used herein includes humans as well asother mammals. In particular, the present invention provides polymericcompositions for the removal of potassium ions. Preferably, thesecompositions are used for the removal of potassium ions from thegastrointestinal tract of animal subjects.

One aspect of the invention is a method of removing potassium ions witha potassium-binding polymeric composition. In one embodiment, thepotassium-binding polymeric composition has high capacity and/orselectivity for binding potassium and does not significantly release thebound potassium in the gastrointestinal tract. It is preferred that thepolymeric composition exhibit selective binding for potassium ions.

It is preferred that the polymeric compositions of the present inventionexhibit high capacity and/or selectivity for potassium ions. The term“high capacity” as used herein encompasses an average in vivo binding ofabout 1.5 mmol or more of potassium per gm of polymer. Typically, thisin vivo binding capacity is determined in a human. Techniques fordetermining in vivo potassium binding capacity in a human are well knownin the art. For example, following administration of a potassium-bindingpolymer to a patient, the amount of potassium in the feces can be usedto calculate the in vivo potassium binding capacity. The average in vivobinding is preferably calculated in a set of normal human subjects, thisset being about 5 human subjects, preferably about 10 human subjects,even more preferably about 25 human subjects, and most preferably about50 human subjects.

In some embodiments, the average in vivo potassium binding capacity canbe equal to or more than about 1.5 mmol per gm of polymer in a human.Preferably the in vivo potassium binding capacity in a human is about 2mmol or more per gm, more preferred is about 3 mmol or more per gm, evenmore preferred is about 4 mmol or more per gm, and most preferred isabout 6 mmol or more per gin. In a preferred embodiment, the average invivo potassium binding capacity in a human is about 2 mmol to about 6mmol per gm in a human.

The capacity of the potassium binding polymers can also be determined invitro. It is preferred that the in vitro potassium binding capacity isdetermined in conditions that mimic the physiological conditions of thegastro-intestinal tract, in particular the colon. In some embodiments,the in vitro potassium binding capacity is determined in solutions witha pH of about 5.5 or more. In various embodiments, in vitro potassiumbinding capacity in a pH of about 5.5 or more is equal to or more than 6mmol per gin of polymer. A preferred range of in vitro potassium bindingcapacity in a pH of about 5.5 or more is about 6 mmol to about 12 mmolper gm of polymer. Preferably the in vitro potassium binding capacity ina pH of about 5.5 or more is equal to about 6 mmol or more per gm, morepreferred is about 8 mmol or more per gm, even more preferred is about10 mmol or more per gm, and most preferred is about 12 mmol or more pergm.

The higher capacity of the polymeric composition enables theadministration of a lower dose of the composition. Typically the dose ofthe polymeric composition used to obtain the desired therapeutic and/orprophylactic benefits is about 0.5 gm/day to about 25 gm/day. Mostpreferred is about 15 gm/day or less. A preferred dose range is about 5gm/day to about 20 gm/day, more preferred is about 5 gm/day to about 15gm/day, even more preferred is about 10 gm/day to about 20 gm/day, andmost preferred is about 10 gm/day to about 15 gm/day. Preferably thedose is administered about three times a day with meals, most preferablythe dose is administered once a day.

It is also preferred that the compositions described herein retain asignificant amount of the bound potassium. Preferably, the potassium isbound by the polymer in the colon and not released prior to excretion ofthe polymer in the feces. The term “significant amount” as used hereinis not intended to mean that the entire amount of the bound potassium isretained. It is preferred that at least some of the bound potassium isretained, such that a therapeutic and/or prophylactic benefit isobtained. Preferred amounts of bound potassium that can be retainedrange from about 5% to about 100%. It is preferred that the polymericcompositions retain about 25% of the bound potassium, more preferred isabout 50%, even more preferred is about 75% and most preferred isretention of about 100% of the bound potassium. The period of retentionis preferred to be during the time that the composition is being usedtherapeutically and/or prophylactically. In the embodiment in which thecomposition is used to bind and remove potassium from thegastrointestinal tract, the retention period is the time of residence ofthe composition in the gastro-intestinal tract and more particularly theaverage residence time in the colon.

Preferably the potassium binding polymers are not absorbed from thegastro-intestinal tract. The term “non-absorbed” and its grammaticalequivalents is not intended to mean that the entire amount ofadministered polymer is not absorbed. It is expected that certainamounts of the polymer may be absorbed. It is preferred that about 90%or more of the polymer is not absorbed, preferably about 95% or more isnot absorbed, even more preferably about 97% or more is not absorbed,and most preferably about 98% or more of the polymer is not absorbed.

Potassium-Binding Polymers

In some embodiments, the potassium-binding polymers comprise acid groupsin their protonated or ionized form, such as sulfonic (—SO₃ ⁻), sulfuric(—OSO₃ ⁻), carboxylic (—CO₂ ⁻), phosphonic (—PO₃ ⁻⁻), phosphoric (—(OPO₃⁻⁻), or sulfamate (—NHSO₃ ⁻). Preferably, the fraction of ionization ofthe acid groups is greater than about 75% at the physiological pH in thecolon and the potassium binding capacity is greater than about 5mmol/gm. Preferably the ionization of the acid groups is greater thanabout 80%, more preferably it is greater than about 90%, and mostpreferably it is about 100%. In certain embodiments the acid containingpolymers contain more than one type of acid groups. In certainembodiments the acid containing polymers are administered in theiranhydride form and generate the ionized form when contacted withphysiological fluids.

In some other embodiments, a pK_(a)-decreasing group, preferably anelectron-withdrawing substituent, is located adjacent to the acid group,preferably it is located in the alpha or beta position of the acidgroup. The preferred electron-withdrawing substituents are a hydroxylgroup, an ether group, an ester group, or an halide atom, and mostpreferably F. Preferred acid groups are sulfonic (—SO₃ ⁻), sulfuric(—OSO₃ ⁻), carboxylic (—CO₂ ⁻), phosphonic (—PO₃ ⁻⁻), phosphoric (—(OPO₃⁻⁻), or sulfamate (—NHSO₃ ⁻). Other preferred polymers result from thepolymerization of alpha-fluoro acrylic acid, difluoromaleic acid, or ananhydride thereof.

Examples of other suitable monomers for potassium-binding polymers areincluded in Table 1.

TABLE 1 Examples of cation exchange moieties - structures & theoreticalbinding capacities Fraction of Fraction of Expected Molar mass perTheoretical titrable H titrable H Capacity Expected Capacity chargecapacity @ pH 3 @ pH 6 @ pH 3 @ pH 6

71 14.1 0.05 .35 0.70 4.93

87 11.49 0.2 0.95 2.3 10.92

53 18.9 0.25 0.5 4.72 9.43

47.5 21.1 0.25 0.5 5.26 10.53

57 17.5 0.1 0.5 1.75 8.77

107 9.3 1 1 9.35 9.35

93 10.8 1 1 10.75 10.75

63 15.9 0 0.4 0 6.35

125 8 1 1 8 8

183 5.5 1 1 5.46 5.46

87 11.49 .1 .6 1.14 6.89

Other suitable cation exchange moieties include:

wherein is equal to or greater than one and Z represents either SO₃H orPO₃H. Preferably n is about 50 or more, more preferably n is about 100or more, even more preferred is n about 200 or more, and most preferredis n about 500 or more.

Suitable phosphonate monomers include vinyl phosphonate, vinyl 1,1 bisphosphonate, and ethylenic derivatives of phosphonocarboxylate esters,oligo(methylenephosphonates), and hydroxyethane-1,1-diphosphonic acid.Methods of synthesis of these monomers are well known in the art.

Sulfamic (i.e. when Z═SO₃H) or phosphoramidic (i.e. when Z═PO₃H)polymers can be obtained from amine polymers or monomer precursorstreated with a sulfonating agent such as sulfur trioxide/amine adductsor a phosphonating agent such as P₂O₅, respectively. Typically, theacidic protons of phosphonic groups are exchangeable with cations, likesodium or potassium, at pH of about 6 to about 7.

Free radical polymers derived from monomers such as vinyl sulfonate,vinylphosphonate, or vinylsulfamate can also be used.

Preferred monomers for use herein are α-fluoroacrylate anddifluoromaleic acid, α-fluoroacrylate being most preferred. This monomercan be prepared from a variety of routes, see for example, Gassen et al,J. Fluorine Chemistry, 55, (1991) 149-162, K F Pittman, C. U., M. Ueda,et al. (1980). Macromolecules 13(5): 1031-1036. Difluoromaleic acid ispreferred by oxidation of fluoroaromatic compounds (Bogachev et al,Zhurnal Organisheskoi Khimii, 1986, 22(12), 2578-83), or fluorinatedfurans derivatives (See U.S. Pat. No. 5,112,993). A preferred mode ofsynthesis of α-fluoroacrylate is given in EP 415214.

Other methods comprise the step-growth polymerization from phosphonate,carboxylic, phosphate, sulfinate, sulfate and sulfonate functionalscompounds. High density polyphosphonates such as Briquest, marketed byRhodia, are particularly useful.

The polymers of the invention also include ion exchange resinssynthesized from naturally occurring polymers, such as saccharidepolymers and semi-synthetic polymers, optionally functionalized tocreate ion exchange sites on the backbone or on the pendant residues.Examples of polysaccharides of interest include materials from vegetalor animal origins, such as cellulosic materials, hemicellulose, alkylcellulose, hydroxyalkyl cellulose, carboxymethylcellulose,sulfoethylcellulose, starch, xylan, amylopectine, chondroitin,hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin andchitosan. Most preferred are polymers that do not degrade under thephysiological conditions of the gastrointestinal tract and remainnon-absorbed, such as carboxymethylcellulose, chitosan, andsulfoethylcellulose.

The potassium binding polymer can be encased in a dialysis bag, paperbag, microporous matrix, polymer gel, hollow fibers, vesicles, capsules,tablet, or a film.

The polymers can be formed by polymerization processes using eitherhomogeneous or heterogeneous mode: in the former case a crosslinked gelis obtained by reacting the soluble polymer chains with a crosslinker,forming a bulk gel which is either extruded and micronized, orcomminuted to smaller sized particles. In the latter case, the particlesare obtained by emulsification or dispersion of a soluble polymerprecursor, and subsequently crosslinked. In another method, theparticles are prepared by polymerization of a monomer in an emulsion,suspension, miniemulsion or dispersion process. The continuous phase iseither an aqueous vehicle or an organic solvent. When a suspensionprocess is used, any suitable type of variants is possible, includingmethods such as “templated polymerization,” “multistage'seededsuspension,” all of which yielding mostly monodisperse particles. In oneparticular embodiment, the beads are formed using a “jetting” process(see U.S. Pat. No. 4,427,794), whereby a “tube of liquid containing amonomer plus initiator mixture is forced through a vibrating nozzle intoa continuous phase. The nozzles can be arranged in spinning turret so asto force the liquid under centrifugal force.

A preferred process to produce alpha-fluoroacrylate beads is directsuspension polymerization. Typically, suspension stabilizers, such aspolyvinyl alcohol, are used to prevent coalescence of particles duringthe process. It has been observed that the addition of NaCl in theaqueous phase decreased coalescence and particle aggregation. Othersuitable salts for this purpose include salts that solubilize in theaqueous phase. In this embodiment, water soluble salts are added at aweight % comprised between about 0.1 to about 10, preferably comprisedbetween about 2 to about 5 and even more preferably between about 3 andabout 4.

It has been observed that in the case of alpha-fluoroacrylate esters(e.g. MeFA) suspension polymerization, the nature of the free radicalinitiator plays a role in the quality of the suspension in terms ofparticle stability, yield of beads, and the conservation of a sphericalshape. Use of water-insoluble free radical initiators, such as laurylperoxide, led to the quasi absence of gel and produced beads in a highyield. It was found that free radical initiators with water solubilitylower than 0.1 g/L preferably lower than 0.01 g/L led to optimalresults. In preferred embodiments, polyMeFA beads are produced with acombination of a low water solubility free radical initiator and thepresence of salt in the aqueous phase, such as NaCl.

In some embodiments wherein the potassium binding polymer is usedwithout a shell, the potassium binding polymer is not Kayexalate, sodiumpolystyrene sulfonate, or an ammonium form of polystyrene sulfonate.

In some embodiments, crown ethers and crown-ether like molecules areused as potassium binding polymers. Crown ethers show selectivity forcertain alkali metals over others, based on the hole-size and the sizeof the metal ion. See Tables 2, 3 and 4 and Pedersen, C. J. 1987.Charles J. Pederson—Nobel Lecture. The discovery of crown ethers. InNobel Lectures, Chemistry 1981-1990. T. Frangsmyr, editor. WorldScientific Publishing Co., Singapore.

In yet another embodiment, crown ethers are used as shell materials todecrease the passage of sodium, magnesium, calcium and other interferingmolecules to the core and as a result, increase the in vivo bindingcapacity of a core polymer.

TABLE 2 Diameters of holes in Sample Crown Ethers, in Angstrom unitsMacrocyclic Polyethers Diameters All 14-crown-4 1.2-1.5 All 15-crown-51.7-2.2 All 18-crown-6 2.6-3.2 All 21-crown-7 3.4-4.3

TABLE 3 Complexable cations and their diameters in Angstrom units GroupI Group II Group III Group IV Li 1.36 Na 1.94 K 2.66 Ca 1.98 Cu(I) 1.92Zn 1.48 Rb 2.94 Sr 2.26 Ag 2.52 Cd 1.94 Cs 3.34 Ba 2.68 La 2.30 Au(I)2.88 Hg(II) 2.20 Tl(I) 2.80 Pb(II) 2.40 Fr 3.52 Ra 2.80 NH₄ 2.86

TABLE 4 Relative binding of sample alkali metal ions by sample crownethers Polyether Li⁺ Na⁺ K⁺ Cs⁺ Dicyclohexyl-14-crown-4 1.1 0 0 0Cyclohexyl-15-crown-5 1.6 19.7 8.7 4.0 Dibenzo-18-crown-6 0 1.6 25.2 5.8Dicyclohexyl-18-crown-6 3.3 25.6 77.8 44.2 Dicyclohexyl-21-crown-7 3.122.6 51.3 49.7 Dicyclohexyl-24-crown-8 2.9 8.9 20.1 18.1

The potassium binding polymers typically include cationic counterions.The cations can be metallic, non-metallic, or a combination thereof.Examples of metallic ions include, but are not limited to, Ca²⁺-form,H⁺-form, NH⁴⁺-form, Na⁺-form, or a combination thereof. Examples ofnon-metallic ions include, but are not limited to, alkylammonium,hydroxyalkylammonium, choline, taurine, camitine, guanidine, creatine,adenine, and aminoacids or derivatives thereof.

In preferred embodiments, the potassium binding polymers describedherein have a decreased tendency to cause side-effects such ashypernatremia and acidosis due to the release of detrimental ions. Theterm “detrimental ions” is used herein to refer to ions that are notdesired to be released into the body by the compositions describedherein during their period of use. Typically, the detrimental ions for acomposition depend on the condition being treated, the chemicalproperties, and/or binding properties of the composition. For example,the detrimental ion could be H⁺ which can cause acidosis or Na⁺ whichcan cause hypernatremia. Preferably the ratio of potassium bound todetrimental cations introduced is 1: about 2.5 to about 4.

Core-Shell Compositions

In one aspect of the invention, a core-shell composition is used for theremoval of potassium. Typically in the core-shell compositions, the corecomprises a potassium-binding polymer, preferably the polymer beingcapable of binding potassium with a high binding capacity. The variouspotassium-binding polymers described herein can be used as the corecomponent of the core-shell compositions. In some embodiments, the shellmodulates the entry of competing solutes such as magnesium and calciumacross the shell to the core component. In one embodiment, thepermeability of the membrane to divalent cations is diminished bydecreasing the porosity to large hydrated cations such as alkaline-earthmetals ions, and by incorporating positive charges that createelectrostatic repulsion with said multivalent cations. It is preferredthat the shell of the core-shell composition is essentially notdisintegrated during the period of residence and passage through thegastro-intestinal tract.

The term “competing solute” as used herein means solutes that competewith potassium for binding to a core component, but that are not desiredto be contacted and/or bound to the core component. Typically, thecompeting solute for a core-shell composition depends on the bindingcharacteristics of the core and/or the permeability characteristics ofthe shell component. A competing solute can be prevented from contactingand/or binding to a core-shell particle due to the preferential bindingcharacteristics of the core component and/or the decreased permeabilityof the shell component for the competing solute from the externalenvironment. Typically, the competing solute has a lower permeabilityfrom the external environment across the shell compared to that ofpotassium ions. Examples of competing solutes include, but are notlimited to, Mg⁺⁺, Ca⁺⁺, and protonated amines.

In some embodiments, the shell is permeable to both mono- and di-valentcations. In some of the embodiments in which the shell is permeable toboth mono- and di-valent cations, the core binds preferably mono-valentcations, preferably potassium, due to the binding characteristics of thecore. In other embodiments, the shell exhibits preferred permeability topotassium ions.

It is particularly preferred that the core-shell compositions and thepotassium binding polymeric compositions described herein bind potassiumin the parts of the gastro-intestinal (GI) tract which have a relativelyhigh concentration of potassium, such as in the colon. This boundpotassium is then preferred to remain bound to the compositions and beexcreted out of the body.

In one embodiment, the shell material protects the core component fromthe external GI environment. The shell material in some embodimentsprotects the acid groups of the core polymer and prevents their exposureto the GI environment. In one embodiment, the core component isprotected with a shell component comprising of an enteric coating.Suitable examples of enteric coatings are described in the art. Forexample, see Remington: The Science and Practice of Pharmacy by A. R.Gennaro (Editor), 20^(th) Edition, 2000.

In another embodiment the shell material is engineered to impose a lowerpermeability to higher valency cations. The permeability of the shell toalkaline-earth cations is altered by changing the average pore size,charge density and hydrophobicity of the membrane. Mg⁺⁺ and Ca⁺⁺hydrated ions have a large size compared with monovalent cations such asK⁺ and Na⁺ as indicated below in Table 5 (Nightingale E. R., J. Phys.Chem., 63, (1959), 1381-89).

TABLE 5 Metal ions Hydrated radii (angstroms) K⁺ 3.31 NH₄ ⁺ 3.31 Na⁺3.58 Mg⁺⁺ 4.28 Ca²⁺ 4.12

Methods to reduced permeabilities to divalent cations are known fromprevious studies on cation-exchange membranes for electrodialysis (e.g.Sata et al, J. Membrane Science, 206 (2002), 31-60). Such methods areusually based on pore size exclusion and electrostatic interaction andcombination thereof.

Accordingly, in some embodiments, several characteristics of the shellcomponent are tuned so that a permeation difference is established. Forexample, when the mesh size of the shell material is in the same sizerange as the solute dimensions, the random walk of a bulkier divalentcation through the shell component is significantly slowed down. Forexample, experimental studies (Krajewska, B., Reactive and Functionalpolymers 47, 2001, 37-47) report permeation coefficients in celluloseester or crosslinked chitosan gel membranes for both ionic and non-ionicsolutes shows slowing down of bulkier solutes when mesh size nearssolute dimensions. The polymer volume fraction in the swollen resin is agood indicator of the mesh size within the composition; theoreticalstudies have shown, for example, that mesh size usually scales withφ^(−3/4), φ being the polymer volume fraction in the shell componentwhen swollen in a solution. The membrane swelling ratio depends on thehydrophobicity, crosslinking density, charge density, and solvent ionicstrength.

For instance polypyrrole layered on the cation exchange materials byin-situ polymerization of pyrrole, is shown to induce permselectivity bycreating a very tightly porous membrane that hinders large divalentcation diffusion relatively to monovalent cations.

Alternatively, a thin layer of a cationic polyelectrolyte is physicallyadsorbed to create a strong electrical field that repel highly chargedcations such as Mg⁺⁺ and Ca⁺⁺. Suitable cationic polyelectrolytesinclude, but are not limited to, copolymers with a repeat unit selectedfrom vinylamine, ethyleneimine, propyleneimine, allylamine,vinylpyridines, alkyaminoalkyl(meth)acrylates,alkyaminoalkyl(meth)acrylamides, aminomethylstyrene, chitosan, adductsof aliphatic amine or aromatic amine with electrophiles such asepichlorhydrine, alkylhalides or epoxydes, and wherein the amine isoptionally a quarternized form. Adducts of aliphatic amine or aromaticamine with alkyldihalides are also referred to as ionenes. The polymericpermselectivity can also be controlled by pH, whereupon the polymercharge density and swelling ratio varies with the rate of(de)protonation.

pH-controlled binding selectivity is an important lever when thecounter-ion initially loaded in the polymer has to be displaced andeventually replaced by potassium. If the polymer is first conditionedwith Ca⁺⁺, a divalent cation with a high binding constant to carboxylicor sulfonic groups, one can take advantage of the acidic environmentencountered in the stomach to protonate the binding sites of the polymerso as to displace the initially loaded counter-ion (i.e. Ca⁺⁺). In thatcontext, it is advantageous to design polymers with ion exchangeproperties varying with the local pH, more preferably polymers with alow binding capacity at gastric pH and a high capacity at pH greaterthan about 5.5. In one preferred embodiment, the polymers of theinvention have a fraction of capacity available at pH lower than about3, of about 0-10% of the full capacity (i.e. measure at pH about 12),and greater than about 50% at pH greater than about 4.

In some embodiments, a shell of a cationic polyelectrolyte is physicallyadsorbed to create a strong electrical field that repels highly chargedcations such as Mg⁺⁺ and Ca⁺⁺. Suitable cationic polyelectrolytesinclude, but are not limited to, copolymers with a repeat unit selectedfrom vinylamine, ethyleneimine, propyleneimine, allylamine,vinylpyridines, alkyaminoalkyl(meth)acrylates,alkyaminoalkyl(meth)acrylamides, aminomethylstyrene, chitosan, adductsof aliphatic amine or aromatic amine with electrophiles such asepichlorhydrine, alkylhalides or epoxydes, and wherein the amine isoptionally a quarternized form. Adducts of aliphatic amine or aromaticamine with alkyldihalides are also referred to as ionenes. The polymericpermselectivity can also be controlled by pH, whereupon the polymercharge density and swelling ratio varies with the rate of(de)protonation. The polymer is held on the core through physical bonds,chemical bonds, or a combination of both. In the former case, theelectrostatic interaction between negatively charged core and positivelycharged shell maintains the core-shell assembly during transit in the GItract. In the latter case a chemical reaction is carried out at thecore-shell interface to prevent “delamination” of the shell material.

Preferably, the shell has a permselectivity factor (i.e. binding rate ofK⁺ vs. other competing ions) above a certain value during the residencetime of the composition in the large bowel. Not intending to be limitedto one mechanism of action, it is believed that the selectivitymechanism hinges on a kinetic effect (as opposed to a pure thermodynamicmechanism for the binding event in the core). That is, if the core-shellparticles of the invention are let to equilibrate for a period of timein the colon, it is predicted that the core-shell will eventually bindcations with a similar profile to the core alone. Hence, in oneembodiment the shell material keeps the rate of permeation for thetarget ions (e.g. K⁺) high enough so that said target ions fullyequilibrates during the mean average residence time in the colon, whilethe rate of permeation of competing cations (e.g. Mg²⁺, Ca²⁺) is lower.This feature is defined as the time persistence of permselectivity. Inthis embodiment, the time persistence can be the time needed to reachbetween about 20% and about 80% (i.e., t₂₀, to t₈₀) of the bindingcapacity at equilibrium in conditions reflecting the colon electrolyteprofile. Typically, for K⁺ (and monovalent cations in general), t₈₀, ispreferably lower than about 5 hrs, more preferably lower than about 2hrs. While for Mg (and multivalent cations in general), t₂₀, ispreferably greater than about 24 hrs, most preferably about 40 hrs.

In another embodiment, the interaction of the positively charged shellwith some of the hydrophobic anions present the GI can achieve a higherlevel of persistence (as measured as an increase in t₈₀ value for Mg²⁺and Ca²⁺). Such hydrophobic anions include bile acids, fatty acids andanionic protein digests. Alternatively anionic surfactants can providethe same benefit. In this embodiment the core-shell material is eitheradministered as is, or formulated with fatty acids or bile acids saltsor even synthetic anionic detergents such as, but not limited to, alkylsulfate, alkyl sulfonate, and alkylaryl sulfonate.

In systems which combine positive charges and hydrophobicity, preferredshell polymers include amine functional polymers, such as thosedisclosed above, which are optionally alkylated with hydrophobic agents.

Alkylation involves reaction between the nitrogen atoms of the polymerand the alkylating agent (usually an alkyl, alkylaryl group carrying anamine-reactive electrophile). In addition, the nitrogen atoms which doreact with the alkylating agent(s) resist multiple alkylation to formquaternary ammonium ions such that less than 10 mol % of the nitrogenatoms form quaternary ammonium ions at the conclusion of alkylation.

Preferred alkylating agents are electrophiles such as compounds bearingfunctional groups such as halides, epoxides, esters, anhydrides,isocyanate, or αβ-unsaturated carbonyls. They have the formula RX whereR is a C1-C20 alkyl (preferably C4-C20), C1-C20 hydroxy-alkyl(preferably C4-C20 hydroxyalkyl), C6-C20 aralkyl, C1-C20 alkylammonium(preferably C4-C20 alkyl ammonium), or C1-C20 alkylamido (preferablyC4-C20 alkyl amido) group and X includes one or more electrophilicgroups. By “electrophilic group” it is meant a group which is displacedor reacted by a nitrogen atom in the polymer during the alkylationreaction. Examples of preferred electrophilic groups, X, include halide,epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups,the alkylation reaction causes opening of the three-membered epoxy ring.

Examples of preferred alkylating agents include a C3-C20 alkyl halide(e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decylhalide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, andcombinations thereof); a C1-C20 hydroxyalkyl halide (e.g., an11-halo-1-undecanol); a C1-C20 aralkyl halide (e.g., a benzyl halide); aC1-C20 alkyl halide ammonium salt (e.g., a (4-halobutyl)trimethylammonium salt, (6-halohexyl)trimethyl-ammonium salt,(8-halooctyl)trimethylammonium salt, (10-halodecyl)trimethylammoniumsalt, (12-halododecyl)-trimethylammonium salts and combinationsthereof); a C1-C20 alkyl epoxy ammoniumn salt (e.g., a(glycidylpropyl)-trimethylammonium salt); and a C1-C20 epoxy alkylamide(e.g., an N-(2,3-eoxypropane)butyramnide,N-(2,3-epoxypropane)hexanamide, and combinations thereof). Benzylehalide and dodecyl halide are more preferred.

The alkylation step on the polyamine shell precursor can be carried outin a separate reaction, prior to the application of the shell onto thecore beads. Alternatively the alkylation can be done once the polyamineshell precursor is deposited onto the core beads. In the latter case,the alkylation is preferably performed with an alkylating agent thatincludes at least two electrophilic groups X so that the alkylation alsoinduces crosslinking within the shell layer. Preferred polyfunctionalalkylation agents include di-halo alkane, dihalo polyethylene glycol,and epichlorohydrine. Other crosslinkers containing acyl chlorides,isocyanate, thiocyanate, chlorosulfonyl, activated esters(N-hydroxysuccinimide), carbodiimide intermediates, are also suitable.

Typically, the level of alkylation is adjusted depending upon the natureof the polyamine precursor and the size of the alkyl groups used onalkylation. Some factors that play a role in the level of alkylationinclude:

-   -   a. Insolubility of the shell polymer under conditions of the GI        tract. In particular, the low pH's prevailing in the stomach        tend to solubilize alkylated polyamine polymers whose pH of        ionization is 5 and above. For that purpose higher rate of        alkylation and higher chain length alkyl are preferred. As an        alternative, one may use an enteric coating to protect the shell        material against acidic pH's, said enteric coating is released        when the core-shell beads are progressing in the lower        intestine.    -   b. The permselectivity profile: When the alkylation ratio is low        the persistence of the permselectivity for competing ions (e.g.        Mg²⁺, Ca²⁺) can be shorter than the typical residence time in        the colon. Conversely when the alkylation ratio (or the weight        fraction of hydrophobes) is high then the material becomes        almost impermeable to most inorganic cations, and thus, the rate        of equilibration for K⁺ becomes long.        Preferably, the degree of alkylation is selected by an iterative        approach monitoring the two variables mentioned above.

Methods for determining permeability coefficients are known. Forexample, see, W. Jost, Diffusion in Solids, Liquids and Gases, Acad.Press, New-York, 1960). For example, the ion permeability coefficient ina shell polymer can be measured by casting the polymer as a membraneover a solid porous material, subsequently contacted with aphysiological solution (donor) containing the ions of interest, andmeasuring steady state permeation rates of said ions, across themembrane in the acceptor solution. Membrane characteristics can then beoptimized to achieve the best cooperation in terms of selectivity andpermeation rate kinetics. Structural characteristics of the membrane canbe varied by modifying, for example, the polymer volume fraction (in theswollen membrane), the chemical nature of the polymer(s) and itsproperties (hydrophobicity, crosslinking density, charge density), thepolymer blend composition (if more than one polymer is used), theformulation with additives such as wetting agents, plasticizers, and/orthe manufacturing process.

The permselective membranes of the invention are optimized by studyingtheir permselectivity profile as a function of polymer compositions andphysical characteristics. Permselectivity is preferably measured inconditions close to those prevailing in the milieu of use (e.g. colon).In a typical experiment, the donor solution is a synthetic fluid with anionic composition, osmolality, and pH mimicking the colonic fluid, oralternatively, an animal fluid collected through ileostomy orcoleostomy. In another embodiment, the membrane is sequentiallycontacted with fluids that model the conditions found in the differentparts of the GI tract, i.e. stomach, duodenum, jejunum, and ileum. Inyet another embodiment, the shell is deposited on a cation exchangeresin bead under the proton form by microencapsulation method andcontacted with a sodium hydroxide aqueous solution. By monitoring pH orconductivity the rate of permeation of NaOH across the membrane is thencomputed. In another embodiment the resin is preloaded with lithiumcations and the release of lithium and absorption of sodium, potassium,magnesium, calcium and ammonium are monitored by ion chromatography. Ina preferred embodiment, the permeability ratio of potassium and divalentcations such as Mg⁺⁺ and Ca⁺⁺, measured in aforementioned conditions iscomprised between about 1:0.5 to about 1:0.0001, preferably betweenabout 1:0.2 and about 1:0.01.

In another embodiment, the shell of a core-shell composition displays apermeability selectivity by passive absorption while passing through theupper GI tract. Many components present in the GI tract includingcomponents of the diet, metabolites, secretion, etc. are susceptible toadsorb onto and within the shell in a quasi-irreversible manner and canstrongly modify the permeability pattern of the shell. The vast majorityof these soluble materials are negatively charged and show variouslevels of hydrophobicity. Some of those species have a typicalamphiphilic character, such as fatty acids, phospholipids, bile saltsand can behave as surfactants. Surfactants can adsorb non-specificallyto surfaces through hydrophobic interactions, ionic interaction andcombinations thereof. In this embodiment, this phenomenon is used tochange the permeability of the polymeric composition upon the course ofbinding potassium ions. In one embodiment fatty acids can be used tomodify the permeability of the shell and in another embodiment bileacids can be used. Fatty acids and bile acids both form aggregates(micelles or vesicles) and can also form insoluble complexes when mixedwith positively charged polymers (see e.g. Kaneko et al, MacromolecularRapid Communications (2003), 24(13), 789-792). Both fatty acids and bileacids exhibit similarities with synthetic anionic surfactants andnumerous studies report the formation of insoluble complexes betweenanionic surfactants and cationically charged polymers (e.g. Chen, L. etal, Macromolecules (1998), 31(3), 787-794). In this embodiment, theshell material is selected from copolymers containing both hydrophobicand cationic groups, so that the shell forms a complex with anionicallycharged hydrophobes typically found in the GI tract, such as bile acids,fatty acids, bilirubin and related compounds. Suitable compositions alsoinclude polymeric materials described as bile acids sequestering agents,such as those reported in U.S. Pat. Nos. 5,607,669; 6,294,163; and5,374,422; Figuly et al, Macromolecules, 1997, 30, 6174-6184. Theformation of the complex induces a shell membrane collapse which in turncan lower the diffusion of bulky divalent cations, while preferablyleaving the permeation of potassium unchanged.

In yet another embodiment, the permeability of the shell of a core-shellcomposition is modulated by enzymatic activity in the gastro-intestinaltract. There are a number of secreted enzymes produced by common colonicmicroflora. For example Bacteroides, Prevotella, Porphyromonas, andFusobacterium produce a variety of secreted enzymes includingcollagenase, neuraminidase, deoxyribonuclease [DNase], heparinase, andproteinases. In this embodiment the shell comprises a hydrophobicbackbone with pendant hydrophilic entities that are cleaved off via anenzymatic reaction in the gut. As the enzymatic reaction proceeds, thepolymer membrane becomes more and more hydrophobic, and turns from ahigh swollen state, high permeability rate material to a fully collapsedlow hydration membrane with minimal permeability to bulky hydratedcations such as Mg⁺⁺ and Ca⁺⁺. Hydrophilic entities can be chosen fromnatural substrates of enzymes commonly secreted in the GI tract. Suchentities include amino acids, peptides, carbohydrates, esters, phosphateesters, oxyphosphate monoesters, O— and S-phosphorothioates,phosphoramidates, thiophosphate, azo groups and the like. Examples ofenteric enzymes susceptible to chemically alter the shell polymerinclude, but are not limited to, lipases, phospholipases,carboxylesterase, glycosidases, azoreductases, phosphatases, amidasesand proteases. The shell can be permeable to potassium ions until itenters the proximal colon and then the enzymes present in the proximalcolon can react chemically with the shell to reduce its permeability tothe divalent cations.

In some embodiments, the shell thickness can be between about 0.002micron to about 50 micron, preferably about 0.005 micron to about 20microns. Preferably the shell thickness is more than about 0.5 micron,more preferred is more than about 2 micron, even more preferred is morethan about 5 micron. Preferably the shell thickness is less than about30 micron, more preferred is less than about 20 micron, even morepreferred is less than about 10 micron, and most preferred is less thanabout 5 micron.

The size of the core-shell particles typically range from about 200 nmto about 2 mm, preferably being about 100 microns. Preferably the sizeof the core-shell particles are more than about 1 microns, morepreferred is more than about 10 microns, even more preferred is morethan about 20 microns, and most preferred is more than about 40 microns.Preferably the size of the core-shell particles are less than about 250microns, more preferred is less than about 150 microns, even morepreferred is less than about 100 microns, and most preferred is lessthan about 50 microns.

Synthesis of Core-Shell Particles

In preferred embodiments, the shell is uniformly coated on the corematerial, preferably without pinholes or macroporosity and is lightweight relative to the core material (for example, up to about 20 wt-%).The shell can be anchored to the core and preferably resistant enough tosustain the mechanical constraint such as swelling and compressionencountered during tablet formulation.

The shell can be formed by chemical or non-chemical processes.Non-chemical processes include spray coating, fluid bed coating, solventcoacervation in organic solvent or supercritical CO₂, solventevaporation, spray drying, spinning disc coating, extrusion (annularjet) or layer by layer formation. Examples of chemical processes includeinterfacial polymerization, grafting from, grafting unto, and core-shellpolymerization.

In fluid bed coating, typically the core beads are kept in arecirculating fluidized bed (Wurster type) and sprayed with a coatingsolution or suspension. The coating polymer can be used as a solution inalcohols, ethylacetate, ketones, or other suitable solvents or as latex.Conditions are typically optimized so as to form a tight and homogeneousmembrane layer, and insure that no cracks are formed upon swelling whenthe particles are contacted with the aqueous vehicle. It is preferredthat the membrane polymer can yield to the volume expansion andelongates so as to accommodate the dimension change. Polymer membraneshave an elongation at break greater than 10%, preferably greater than30%. Examples of this approach are reported in Ichekawa H. et al,International Journal of Pharmaceuticals, 216(2001), 67-76.

Solvent coacervation is described in the art. For example, see Leach, K.et al., J. Microencapsulation, 1999, 16(2), 153-167. In this process,typically two polymers, core polymer and shell polymer are dissolved ina solvent which is further emulsified as droplets in an aqueous phase.The droplet interior is typically a homogeneous binary polymer solution.The solvent is then slowly driven off by careful distillation. Thepolymer solution in each droplet undergoes a phase separation as thevolume fraction of polymer increases. One of the polymer migrates to thewater/droplet interface and forms a more-or less perfect core-shellparticle (or double-walled microsphere).

Solvent coacervation is one of the preferred methods to deposit acontrolled film of shell polymer onto the core. In one embodiment, thecoacervation technique consists in dispersing the core beads in acontinuous liquid phase containing the shell material in a soluble form.The coacervation process then consists of gradually changing thesolvency of the continuous phase so that the shell material becomesincreasingly insoluble. At the onset of precipitation some of the shellmaterial ends up as a fine precipitate or film at the bead surface. Thechange in solvency can be triggered by a variety of physical chemistrymeans such as, but not limited to, changes in pH, ionic strength (i.e.osmolality), solvent composition (through addition of solvent ordistillation), temperature (e.g when a shell polymer with a LCST ( lowercritical solution temperature) is used), pressure ( particularly whensupercritical fluids are used). More preferred are solvent coacervationprocesses when the trigger is either pH or solvent composition.Typically when a pH trigger event is used and when the polymer isselected from an amine type material, the shell polymer is firstsolubilized at low pH. In a second step the pH is gradually increased toreach the insolubility limit and induce shell deposition; the pH changeis often produced by adding a base under strong agitation. Anotheralternative is to generate a base by thermal hydrolysis of a precursor(e.g. thermal treatment of urea to generate ammonia). The most preferredcoacervation process is when a ternary system is used comprising theshell material and a solvent/non-solvent mixture of the shell material.The core beads are dispersed in that homogeneous solution and thesolvent is gradually driven off by distillation. The extent of shellcoating can be controlled by on-line or off-line monitoring of the shellpolymer concentration in the continuous phase. In the most common casewhere some shell material precipitates out of the core surface either ina colloidal form or as discrete particle, the core-shell particles areconveniently isolated by simple filtration and sieving. The shellthickness is typically controlled by the initial core to shell weightratio as well as the extent of shell polymer coacervation describedearlier. The core-shell beads can then be annealed to improve theintegrity of the outer membrane as measured by competitive binding.

Supercritical CO₂ coating is described in the art. For example, seeBenoit J. P. et al, J. Microencapsulation, 2003, 20(1)87-128. Thisapproach is somewhat a variant of the solvent coacervation. First theshell coating material is dissolved in the supercritical CO₂, and thenthe active is dispersed in that fluid in super-critical conditions. Thereactor is cooled down to liquid CO₂ conditions wherein the shellmaterial is no longer soluble and precipitates on the core beads. Theprocess is exemplified with shell materials selected from smallmolecules such as waxes and parafins. The core-shell material isrecovered as a powder.

The spinning disc coating technique is based on forming a suspension ofthe core particles in the coating, then using a rotating disc to removethe excess coating liquid in the form of small droplets, while aresidual coating remains around the core-particles. See U.S. Pat. No.4,675,140.

In the layer by layer process, a charged core material is contacted witha polyelectrolyte of opposite charge and a polymer complex is formed.This step is repeated until a multilayer is deposited on the coresurface. Further crosslinking of the layers are optional.

Interfacial polymerization consists of dispersing the core materialcontaining one reacting monomer in a continuous phase containing aco-reacting monomer. A polymerization reaction takes place at the coreinterface creating a shell polymer. The core can be hydrophilic orhydrophobic. Typical monomer used for that purpose can includediacylchlorides/diamines, diisocyanates/diamines, diisocyanates/diols,diacylchlorides/diols and bischloroformate and diamines or diols.Trifunctional monomers can also be used to control the degree ofporosity and toughness of the membranes.

In yet another embodiment, the shell is formed by contacting the ionexchange material with a polymer dispersion of opposite charge (i.e. thecore material is typically charged negatively and the shell positively),and filter the bead particles and anneal them in a fluidized bed at atemperature higher than the transition temperature (or softening point)of the shell polymer. In this embodiment the polymer dispersion is alatex or a polymer colloidal dispersion of particle size in the micronto sub-micron range.

In one further embodiment, the shell material comprises treating theacid containing core material or its derivatives such as methyl ester oracyl chloride with reactive monomer or polymer. Preferably the acidreactive material is a polymer and more preferably a polyamine: forinstance a carboxylated core polymer is treated with polyethyleneimineat high temperature in an organic solvent to create amide bonds betweenthe COOH groups and the NH and NH₂ groups. It can also be useful toactivate the acid functions to facilitate the amide bond formation, e.g.by treating COOH or SO₃H groups with thionylchloride or chlorosulfonicacid to convert said groups into their acid chloride forms. See Sata etal., Die Angewandte Makromolekulare Chemie 171, (1989) 101-117 (Nr2794).

The process of “grafting from” involves an active site capable ofinitiating polymerization on the core surface and polymer chains aregrown from the surface in monolayers. Living polymerization methods suchas nitroxide-mediated living polymerizations, ATRP, RAFT, ROMP are mostsuitable, but non living polymerizations have also been applied.

In the process of “grafting onto” a small molecule (typically anelectrophile, such as epoxy, isocyanate, anhydride, etc.) is brought incontact with the polymeric core material, said core carrying reactivespecies (typically nucleophile groups such as amine, alcohol, etc.). Thethickness of the shell thus formed is controlled by the rate ofdiffusion of the shell small molecule precursor and the rate of reactionwith the core. Slow-diffusing/highly reactive species tend to confinethe reaction within a short distance from the core surface thusproducing a thin shell. Whereas, fast-diffusing/slow reacting speciestend to invade the entire core with no defined shell and form a gradientrather than a sharp shell to core boundary.

Core-shell polymerizations can be emulsion polymerization,suspension/mini-emulsion polymerization, or dispersion polymerization.All these processes employ free radical polymerizations. In emulsionpolymerization, the polymerization takes place in aqueous medium with asurfactant, monomer with a low water solubility, and a water solublefree radical initiator. Polymer particles are formed by micellar orhomogeneous nucleation or both. Core shell particles can be formedtheoretically by feeding the core monomer first and the shell monomersecond as long as the monomer is spontaneously consumed as it is fed(“starved regime”). The potassium binding core beads are preferably madefrom a water insoluble monomer (e.g. alkylester of α-fluoro-acrylicacid).

In suspension/mini-emulsion polymerization, the free radical initiatoris soluble with the monomer. Monomer and initiator are pre-dissolved andthen emulsified in droplet stabilized with either surfactant oramphiphilic polymers. This method allows one pre-formed polymer (e.g.the shell polymer) to be dissolved as well. When the reaction proceeds,the shell polymer and the core polymer phase separate to form thedesired core-shell particles.

In dispersion polymerization, both the monomer and the initiator aresoluble in the continuous phase (usually an organic solvent). A blockcopolymer is used as a steric stabilizer. The polymer particles areformed by homogenous nucleation and subsequent growth. Particle size areon the 1 to 10 microns range and mono-dispersed.

In a preferred process of dispersion, polymerization employs arefinement reported in Stover H. et al, Macromolecules, 1999, 32,2838-2844, described thereafter: The shell monomer contains a largefraction of divinyl monomer, such as 1,4 divinylbenzene, while the coreparticles present some polymerizable double bond on their surface; theshell polymerization mechanism is based on the formation of shortoligoradicals in the continuous phase, which are captured by the doublebond present on the particle surface. The oligomers themselves containnon-reacted insaturation that replenish the surface in reactive doublebonds. The net result is a formation of a crosslinked shell with a sharpboundary with the shell and the core material.

In one embodiment, a core-shell composition of the invention issynthesized by forming the cation exchange core in a conventionalinverse suspension process using suitable monomers; decorating theparticle surface with reactive double bonds by post-reacting with theacidic group present on the particle core; and dispersing in typicaldispersion polymerization solvent such as acetonitrile (e.g. anon-solvent for the cation-exchange core polymer) and adding apolymerizing mixture of DVB or EGDMA with a functional monomer.

In a preferred embodiment, the shell is formed with Eudragit, forexample Eudragit RL 100 or RS 100 or a combination thereof, or withpolyethyleneimine (PEI). These shells maybe applied by solventcoacervation technique. The PEI may be optionally benzylated and alsooptionally cross-linked. Examples of suitable cross-linkers include, butare not limited to,

Methods of Treatments

The methods and compositions described herein are suitable for treatmentof hyperkalemia caused by disease and/or use of certain drugs.

In some embodiments of the invention, the compositions and methodsdescribed herein are used in the treatment of hyperkalemia caused bydecreased excretion of potassium, especially when intake is not reduced.A common cause of decreased renal potassium excretion is renal failure(especially with decreased glomerular filtration rate), often coupledwith the ingestion of drugs that interfere with potassium excretion,e.g., potassium-sparing diuretics, angiotensin-converting enzymeinhibitors (ACEIs), non-steroidal anti-inflammatory drugs, heparin, ortrimethoprim. Impaired responsiveness of the distal tubule toaldosterone, for example in type IV renal tubular acidosis observed withdiabetes mellitus as well as sickle cell disease and/or chronic partialurinary tract obstruction is another cause of reduced potassiumsecretion. Secretion is also inhibited in diffuse adrenocorticalinsufficiency or Addison's disease and selective hypoaldosteronism.Hyperkalemia is common when diabetics develop hypoteninemichypoaldosteronism or renal insufficiency (Mandal, A. K. 1997.Hypokalemia and hyperkalemia. Med Clin North Am. 81:611-39).

In certain preferred embodiments, the potassium binding polymersdescribed herein are administered chronically. Typically, such chronictreatments will enable patients to continue using drugs that causehyperkalemia, such as potassium-sparing diuretics, ACEI's, non-steroidalanti-inflammatory drugs, heparin, or trimethoprim. Also, use of thepolymeric compositions described herein will enable certain patientpopulations, who were unable to use hyperkalemia causing drugs, to usesuch drugs.

In certain chronic use situations, the preferred potassium bindingpolymers used are those that are capable of removing less than about 5mmol of potassium per day or in the range of about 5- about 10 mmol ofpotassium per day. In acute conditions, it is preferred that thepotassium binding polymers used are capable of removing about 15- about60 mmol of potassium per day.

In certain other embodiments, the compositions and methods describedherein are used in the treatment of hyperkalemia caused by a shift fromintracellular to extracellular space. Infection or trauma resulting incell disruption, especially rhabdomyolysis or lysis of muscle cells (amajor potassium store), and tumor lysis can result in acutehyperkalemia. More often, mild-to-moderate impairment of intracellularshifting of potassium occurs with diabetic ketoacidosis, acute acidosis,infusion of argentine or lysine chloride for the treatment of metabolicalkalosis, or infusion of hypertonic solutions such as 50% dextrose ormannitol. β-receptor blocking drugs can cause hyperkalemia by inhibitingthe effect of epinephrine.

In certain other embodiments, the compositions and methods describedherein are used in the treatment of hyperkalemia caused by excessiveintake of potassium. Excessive potassium intake alone is an uncommoncause of hyperkalemia. Most often, hyperkalemia is caused byindiscriminate potassium consumption in a patient with impairedmechanisms for the intracellular shift of potassium or renal potassiumexcretion. For example, sudden death among dialyzed patients who arenoncompliant in diet can be attributed to hyperkalemia.

In the present invention, the potassium-binding polymers and thecore-shell compositions can be co-administered with other activepharmaceutical agents. This co-administration can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.For example, for the treatment of hyperkalemia, the potassium-bindingpolymers and the core-shell compositions can be co-administered withdrugs that cause the hyperkalemia, such as potassium-sparing diuretics,angiotensin-convening enzyme inhibitors, non-steroidal anti-inflammatorydrugs, heparin, or trimethoprim. The drug being co-administered can beformulated together in the same dosage form and administeredsimultaneously. Alternatively, they can be simultaneously administered,wherein both the agents are present in separate formulations. In anotheralternative, the drugs are administered separately. In the separateadministration protocol, the drugs may be administered a few minutesapart, or a few hours apart, or a few days apart.

The term “treating” as used herein includes achieving a therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication, amelioration, or prevention of the underlying disorderbeing treated. For example, in a hyperkalemia patient, therapeuticbenefit includes eradication or amelioration of the underlyinghyperkalemia. Also, a therapeutic benefit is achieved with theeradication, amelioration, or prevention of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a potassium-binding polymer to a patientsuffering from hyperkalemia provides therapeutic benefit not only whenthe patient's serum potassium level is decreased, but also when animprovement is observed in the patient with respect to other disordersthat accompany hyperpkalemia like renal failure. For prophylacticbenefit, the potassium-binding polymers may be administered to a patientat risk of developing hyperpkalemia or to a patient reporting one ormore of the physiological symptoms of hyperpkalemia, even though adiagnosis of hyperpkalemia may not have been made.

The pharmaceutical compositions of the present invention includecompositions wherein the potassium binding polymers are present in aneffective amount, i.e., in an amount effective to achieve therapeutic orprophylactic benefit. The actual amount effective for a particularapplication will depend on the patient (e.g., age, weight, etc.), thecondition being treated, and the route of administration. Determinationof an effective amount is well within the capabilities of those skilledin the art, especially in light of the disclosure herein.

The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievegastrointestinal concentrations that have been found to be effective inanimals.

The dosages of the potassium binding polymers in animals will depend onthe disease being, treated, the route of administration, and thephysical characteristics of the patient being treated. Dosage levels ofthe potassium binding polymers for therapeutic and/or prophylactic usescan be from about 0.5 gm/day to about 30 gm/day. It is preferred thatthese polymers are administered along with meals. The compositions maybe administered one time a day, two times a day, or three times a day.Most preferred dose is about 15 gm/day or less. A preferred dose rangeis about 5 gm/day to about 20 gm/day, more preferred is about 5 gm/dayto about 15 gm/day, even more preferred is about 10 gm/day to about 20gm/day, and most preferred is about 10 gm/day to about 15 gm/day.

In some embodiments, the amount of potassium bound by the core-shallcompositions is greater than the amount if the core component, i.e.,potassium binding polymer is used in the absence of the shall. Hence,the dosage of the core component in some embodiments is lower when usedin combination with a shall compared to when the core is used withoutthe shell. Hence, in some embodiments of the core-shell pharmaceuticalcomposition is less than the amount that is administered to an animal inthe absence of the shall component.

The composition described herein can be used as food products and/orfood additives. They can be added to foods prior to consumption or whilepackaging to decrease levels of potassium. The compositions can also beused in fodder for animals to lower K⁺ levels which is for exampledesirable for example in fodders for pigs and poultry to lower the watersecretion.

Formulations and Routes of Administration

The polymeric compositions and core-shell compositions described hereinor pharmaceutically acceptable salts thereof, can be delivered to thepatient using a wide variety of routes or modes of administration. Themost preferred routes for administration are oral, intestinal, orrectal.

If necessary, the polymers and core-shell compositions may beadministered in combination with other therapeutic agents. The choice oftherapeutic agents than can be co-administered with the compounds of theinvention will depend, in part, on the condition being treated.

The polymers (or pharmaceutically acceptable salts thereof) may beadministered per se or in the form of a pharmaceutical compositionwherein the active compound(s) is in admixture or mixture with one ormore pharmaceutically acceptable carriers, excipients or diluents.Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers compromising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For oral administration, the compounds can be formulated readily bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions wafers, and the like, fororal ingestion by a patient to be treated. In one embodiment, the oralformulation does not have an enteric coating. Pharmaceuticalpreparations for oral use can be obtained as a solid excipient,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients are, in particular, fillerssuch as sugars, including lactose, sucrose, mannitol, or sorbitol;cellulose preparations such as, for example, maize starch, wheat starchrice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores can be provided with suitable coating. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

For administration orally, the compounds may be formulated as asustained release preparation. Numerous techniques for formulatingsustained release preparations are known in the art.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for administration.

In some embodiments the polymers of the invention are provided aspharmaceutical compositions in the form of chewable tablets. In additionto the active ingredient, the following types of excipients are commonlyused: a sweetening agent to provide the necessary palatability, plus abinder where the former is inadequate in providing sufficient tablethardness; a lubricant to minimize frictional effects at the die wall andfacilitate tablet ejection; and, in some formulations a small amount ofa disintegrant is added to facilitate mastication. In general excipientlevels in currently-available chewable tablets are on the order of 3-5fold of active ingredient(s) whereas sweetening agents make up the bulkof the inactive ingredients.

The present invention provides chewable tablets that contain a polymeror polymers of the invention and one or more pharmaceutical excipientssuitable for formulation of a chewable tablet. The polymer used inchewable tablets of the invention preferably has a swelling ratio whiletransiting the oral cavity and in the esophagus of less than about 5,preferably less than about 4, more preferable less than about 3, morepreferably less than 2.5, and most preferably less than about 2. Thetablet comprising the polymer, combined with suitable excipients,provides acceptable organoleptic properties such as mouthfeel, taste,and tooth packing, and at the same time does not pose a risk to obstructthe esophagus after chewing and contact with saliva.

In some aspects of the invention, the polymer(s) provide mechanical andthermal properties that are usually performed by excipients, thusdecreasing the amount of such excipients required for the formulation.In some embodiments the active ingredient (e.g., polymer) constitutesover about 30%, more preferably over about 40%, even more preferablyover about 50%, and most preferable more than about 60% by weight of thechewable tablet, the remainder comprising suitable excipient(s). In someembodiments the polymer comprises about 0.6 gm to about 2.0 gm of thetotal weight of the tablet, preferable about 0.8 gm to about 1.6 gm. Insome embodiments the polymer comprises more than about 0.8 gm of thetablet, preferable more than about 1.2 gm of the tablet, and mostpreferably more than about 1.6 gm of the tablet. The polymer is producedto have appropriate strength/friability and particle size to provide thesame qualities for which excipients are often used, e.g., properhardness, good mouth feel, compressibility, and the like. Unswelledparticle size for polymers used in chewable tablets of the invention isless than about 80, 70, 60, 50, 40, 30, or 20 microns mean diameter. Inpreferred embodiments, the unswelled particle size is less than about80, more preferably less than about 60, and most preferably less thanabout 40 microns.

Pharmaceutical excipients useful in the chewable tablets of theinvention include a binder, such as microcrystalline cellulose,colloidal silica and combinations thereof (Prosolv 90), carbopol,providone and xanthan gum; a flavoring agent, such as sucrose, mannitol,xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such asmagnesium stearate, stearic acid, sodium stearyl fumurate and vegetablebased fatty acids; and, optionally, a disintegrant, such ascroscarmellose sodium, gellan gum, low-substituted hydroxypropyl etherof cellulose, sodium starch glycolate. Other additives may includeplasticizers, pigments, talc, and the like. Such additives and othersuitable ingredients are well-known in the art; see, e.g., Gennaro AR(ed), Remington's Pharmaceutical Sciences, 20^(th) Edition.

In some embodiments the invention provides a pharmaceutical compositionformulated as a chewable tablet, comprising a polymer described hereinand a suitable excipient. In some embodiments the invention provides apharmaceutical composition formulated as a chewable tablet, comprising apolymer described herein, a filler, and a lubricant. In some embodimentsthe invention provides a pharmaceutical composition formulated as achewable tablet, comprising a polymer described herein, a filler, and alubricant, wherein the filler is chosen from the group consisting ofsucrose, mannitol, xylitol, maltodextrin, fructose, and sorbitol, andwherein the lubricant is a magnesium fatty acid salt, such as magnesiumstearate.

The tablet may be of any size and shape compatible with chewability andmouth disintegration, preferably of a cylindrical shape, with a diameterof about 10 mm to about 40 mm and a height of about 2 mm to about 10 mm,most preferable a diameter of about 22 mm and a height of about 6 mm.

In one embodiment, the polymer is pre-formulated with a high Tg/highmelting point low molecular weight excipient such as mannitol, sorbose,sucrose in order to form a solid solution wherein the polymer and theexcipient are intimately mixed. Method of mixing such as extrusion,spray-drying, chill drying, lyophilization, or wet granulation areuseful. Indication of the level of mixing is given by known physicalmethods such as differential scanning calorimetry or dynamic mechanicalanalysis.

Methods of making chewable tablets containing pharmaceuticalingredients, including polymers, are known in the art. See, e.g.,European Patent Application No. EP373852A2 and U.S. Pat. No. 6,475,510,and Remington's Pharmaceutical Sciences, which are hereby incorporatedby reference in their entirety.

In some embodiments the polymers of the invention are provided aspharmaceutical compositions in the form of liquid formulations. In someembodiments the pharmaceutical composition contains an ion-bindingpolymer dispersed in a suitable liquid excipient. Suitable liquidexcipients are known in the art; see, e.g., Remington's PharmaceuticalSciences.

EXAMPLES Example 1 Preparation of Polymers with High Binding Capacity

Materials:

All chemicals were purchased from commercial sources and used asreceived. All reactions were carried out under nitrogen. Chemicalstructures and used abbreviations are given below in Tables 6 and 7.

TABLE 6 Monomer Abbreviations and Structures Abbrevia- Molecular tionChemical name Structure Weight CAS # Na-VSA vinylsulfonic acid sodiumsalt

130.1 3039-83-6 FAA 2-fluoroacrylic acid or α-fluoroacrylic acid or2-fluoropropenoic acid

90.05  430-99-9 VPA vinylphosphonic acid

108.03 1746-03-8

TABLE 7 Crosslinker Abbreviations and Structures Molecular AbbreviationChemical name Structure Weight CAS # X-V-1 ethylenebisacrylamide

168.2  2956-58-3 X-V-2

310.36 X-V-3

254.33 X-V-4 N,N′- bis(vinylsulfonylacetyl) ethylene diamine

324.38 66710-66-5 X-V-5 1,3-bis(vinylsulfonyl) 2- propanol

240.3 67006-32-0 X-V-6 vinylsulfone

118.15   77-77-0 X-V-7 N,N′- methylenebisacrylamide

154.17  110-26-9 ECH epichlorohydrin

92.52

Initiators: VA-044:2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride; K₂S₂O₈,potassium persulfate

General Procedure for Gel Preparation from FAA:

To a 15-ml test tube were charged FAA, X-V-1, and water, followed by amagnetic stirbar. The mixture was stirred at 45° C. for 20 minutes andVA-044 (100 mg/ml solution in water) was added. The solution gelled andwas kept at 45° C. for 4 hours, then cooled to room temperature.

The gel was transferred to a 50-ml polypropylene tube and water wasadded to a total volume of 30 ml. The gel was crushed with a spatula,and further milled with an Ultra-Turrax. The tube was capped andcentrifuged at 3000 rpm for 30 minutes and the supernatant solution wasdecanted off. To the gel was added 1.0M HCl to a total volume of 45 mland tube was capped and tumbled for 30 minutes. The tube was centrifugedat 3000 rpm for 30 minutes and supernatant solution was decanted off.The same tumbling-centrifuging procedure was repeated once with 1.0M HCland three times with nanopure water. The gel was freeze-dried for threedays. The reaction solution composition and gel yield are displayed inTable 8.

TABLE 8 Synthesis of FAA gels Reaction solution composition FAA X-V-1Water VA-044 Yield Sample # (mg) (mg) (mL) (mL) (mg) 628A 757 19 0.7570.038 740 628B 737 37 0.737 0.037 760 628C 730 73 0.730 0.037 760 628D691 138 0.691 0.035 780General Procedure for Gel Preparation from NaVSA:

Commercially available vinylsulfonic acid, sodium salt (NaVSA) wasconverted into acid form and purified by vacuum distillation accordingto a method described by Breslow et al (J. Am. Chem. Soc., 1954, 76,6399-6401). The pure acid was then dissolved in water and neutralizedwith NaOH solution carefully at 0° C. The colorless salt solution wasconcentrated by vacuum distillation to a concentration of 56 wt. %.

To a 15-ml test tube were charged NaVSA solution, crosslinker, and amagnetic stirbar and the mixture was stirred at 45° C. for 20 minutes.VA-044 (50 mg/mL solution in water) or K₂S₂O₈ (50 mg/mL solution inwater) was added. The solution was stirred at 45° C. (if VA-044 used) or50° C. (if K₂S₂O₈ used) for 16 hours, then cooled to room temperature.The gel was purified according to the same procedure as used for FAAgel. The reaction solution composition and gel yield were displayed inTable 9.

TABLE 9 Synthesis of NaVSA gels Reaction solution composition NaVSAX-V-1 X-V-5 VA-044 K₂S₂O₈ Yield Sample # (mL) (mg) (mg) (mL) (mL) (mg)100851A1 1.493 28 0 0.056 0 0 100851A2 1.493 56 0 0.056 0 400 100851A31.493 112 0 0.056 0 740 100851A4 1.493 225 0 0.056 0 590 100851B1 1.4930 28 0.056 0 550 100851B2 1.493 0 56 0.056 0 830 100851B3 1.493 0 1120.056 0 890 100851B4 1.493 0 225 0.056 0 800 100851C1 1.493 28 0 0 0.0560 100851C2 1.493 56 0 0 0.056 420 100851C3 1.493 112 0 0 0.056 760100851C4 1.493 225 0 0 0.056 730 100851D1 1.493 0 28 0 0.056 390100851D2 1.493 0 56 0 0.056 540 100851D3 1.493 0 112 0 0.056 890100851D4 1.493 0 225 0 0.056 720General Procedure for Gel Preparation from Copolymerization of NaVSA andFAA:

To a 15-ml test tube were charged FAA and NaVSA solution, followed by amagnetic stirbar. The mixture was stirred at room temperature for 10minutes and all FAA dissolved. X-V-1 was added and mixture was stirredat room temperature for 10 minutes, then at 45° C. for 20 minutes.VA-044 (100 mg/ml solution in water) was added and the solution wasstirred at 45° C. for 3 hours, then cooled to room temperature. The gelwas purified according to the same procedure as used for FAA gel. Thereaction solution composition and gel yield were displayed in Table 10.

TABLE 10 Synthesis of NaVSA/FAA gels Reaction solution composition FAANaVSA X-V-1 Va-044 Yield Sample # (mg) (mL) (mg) (mL) (mg) 101028A1 01.328 100 0.100 600 101028A2 100 1.195 100 0.100 630 101028A3 200 1.062100 0.100 720 101028A4 300 0.930 100 0.100 780 101028A5 400 0.797 1000.100 730 101028A6 500 0.664 100 0.100 700General Procedure for Gel Preparation from Copolymerization of AA andFAA:

To a 15-ml test tube containing a magnetic stirbar, were charged FAA,X-V-1 and water, and the mixture was stirred until all solids dissolved.AA was added, followed by VA-044 (100 mg/ml solution in water). Themixture was stirred at 45° C. for 3 hours, then cooled to roomtemperature. The gel was purified according to the same procedure asused for FAA gel. The reaction solution composition and gel yield weredisplayed in Table 11.

TABLE 11 Synthesis of FAA/AA gels Reaction solution composition FAA AAX-V-1 Water VA-044 Yield Sample # (mg) (mL) (mg) (mL) (mL) (mg) 100982A1800 0 80 0.764 0.040 770 100982A2 720 0.076 80 0.764 0.040 700 100982A3640 0.152 80 0.764 0.040 730 100982A4 560 0.228 80 0.764 0.040 740100982A5 480 0.304 80 0.764 0.040 740 100982A6 400 0.380 80 0.764 0.040730General Procedure for Preparation of poly(vinylsulfamate) Gel:

Polyvinylamine hydrochloride (PVAm.HCl) was prepared according to aliterature procedure by Badesso et al (in Hydrophilic Polymers:Performance with Environmental acceptance, P489-504). PVAm gel wasprepared by the crosslinking reaction of PVAm.HCl with epichlorohydrin.The procedure was as follows: to a 100 ml of round bottom flask wascharged 33 wt % PVAm.HCl aqueous solution (15 gm, 62.9 mmol), followedby 50 wt % NaOH solution (2.63 gm) to neutralize 50 mol % of PVAm.HCl.Epichlorohydrin (1.0 gm) was added and the mixture was stirredmagnetically until stirring stopped due to gel formation. The gel wasfurther cured at 65° C. for 12 hours and transferred to a 50-mlpolypropylene tube, and then water was added to a total volume of 30 ml.The gel was crushed with a spatula, and further milled with anUltra-Turrax. The gel was washed with 1M HCl and nanopure water usingthe procedure described for FAA gel. Finally, PVAm gel was freeze driedfor 3 days.

General Procedure for Preparing poly(vinylsulfamate) Gel:

To a 20 ml vial was added 0.5 gm of PVAm gel and 10 ml of solvent. Themixture was heated at 60° C. for 1 hour, then 0.5 gm of sulfur trioxidetrimethylamine (SO₃.N(CH₃)₃) was added. Inorganic base, Na₂CO₃.or 2MNaOH solution, was added to the reaction mixture to maintain the pHabove 9. The mixture was heated at 60° C. for a certain time. Themixture was centrifuged, and supernatant solution was decanted off. Thegel was washed with nanopure water until pH reached 7, and freeze dried.The reaction conditions and the conversion of amine group to sulfamategroup are shown in Table 12.

TABLE 12 Preparation of poly(vinylsulfamate) gel Ratio of (CH₃)₃•SO₃ toReaction Sample # NH₂ Base time (hours) Solvent Conversion (%) 001 1:1None 3 Water 22.4 002 1:1 None 10 Water 37.1 003 1:1 None 22 Water 40.8008   1:1.5 (CH₃)₃N 22 (CH₃)₃N/water 65.5 (20 vol %) 010   1:1.5Pyridine 22 Pyridine/Water 4.84 (20 wt %) 013 1:1 Na₂CO₃ 22 Water 80.5014   1:1.5 Na₂CO₃ 22 Water 86.1 015 1:1 NaOH 22 Water 72.5 016 1.5 NaOH22 water 73.5

Example 2 Binding Capacity Screening Protocol

All experiments were performed in duplicate. Approximately 30 mg of eachpolymer was aliquoted in duplicate into 16×100 mm glass test tubes.Dowex 50W and Amberlite CG-50 were included in each experiment asinternal controls. The relevant test binding buffer (Buffer 1, Buffer 2or Buffer 3 below) was added to a final resin concentration of 2.5mg/ml. The test tubes were sealed using a Teflon membrane and incubatedat room temperature, with constant end-over-end rotation, for at leastone hour to allow the cations to achieve binding equilibrium with thepolymers. The test tubes were then centrifuged at 500 g for thirtyminutes to isolate the resins. A sample of the supernatant was taken andthe equilibrium concentrations of potassium (K⁺ _(eq)) and sodium (Na⁺_(eq)) were determined by Ion Chromatography (IC). By comparing K⁺ _(eq)and Na⁺ _(eq) with the concentration of potassium in Buffer 1, Buffer 2or Buffer 3 in the absence of polymer (K⁺ _(start) and Na⁺ _(start)),the amount of cation (in mmoles cation/gram of polymer) was calculated.The ratio of sodium and potassium bound to the polymer was alsocalculated in this manner.

The capacity of each resin for Sodium and for Potassium was tested undersome or all of the following conditions:

-   -   1. 75 mM NaOH, 75 mM KOH (pH not adjusted)    -   2. 50 mM Citric Acid, 75 mM KOH, 75 mM NaOH, pH6.35 (with HCl)    -   3. 50 mM Citric Acid, 75 mM KOH, 75 mM NaOH, pH 3 (with HCl)

TABLE 13 Binding capacities of phosphonic, carboxylic, and sulfonicpolymers Total mmoles Total Total (Na⁺ + K⁺) mmoles (Na⁺ + K⁺) Na⁺:K⁺mmoles bound/gm Na⁺:K⁺ bound/gm ratio at (Na⁺ + K⁺) Na⁺:K⁺ Sample resin,ratio at resin, pH pH bound/gm ratio at Name Description pH 12.5 pH 12.56.25 6.25 resin, pH 3 pH 3 616B3 NaVSA + 20 wt. % X-V-1 624B NaVSA + 5wt. % X-V-2 624C NaVSA + 10 wt. % X-V-2 6.91 0.76 6.35 0.78 6.43 0.76624D NaVSA + 20 wt. % X-V-2 6.50 0.78 6.20 0.84 5.95 0.81 628A FAA + 2.5wt. % X-V-1 10.44 0.96 9.76 0.98 2.92 0.50 628A FAA + 2.5 wt. % X-V-19.85 0.97 3.45 0.50 628B FAA + 5.0 wt. % X-V-1 10.22 1.01 9.61 1.01 2.930.48 628C FAA + 10 wt. % X-V-1 10.05 1.02 9.36 1.02 2.84 0.47 628C FAA +10 wt. % X-V-1 10.68 0.98 9.18 0.97 2.85 0.42 628C FAA + 10 wt. % X-V-19.87 0.93 9.63 0.85 2.13 0.27 628D FAA + 20 wt. % X-V-1 9.12 1.03 8.521.02 2.59 0.50 629A FAA + 25 mol % NaOH + 12.5 wt. % X-V-1 9.59 1.029.18 1.00 2.87 0.44 10.27 0.99 9.52 0.98 2.79 0.41 629B FAA + 50 mol %NaOH + 12.5 wt. % X-V-1 9.58 1.02 9.05 1.02 2.69 0.38 629B FAA + 50 mol% NaOH + 12.5 wt. % X-V-1 10.06 0.93 9.01 0.85 1.68 0.14 629C FAA + 75mol % NaOH + 12.5 wt. % X-V-1 9.41 0.98 9.33 1.01 3.19 0.54 629D FAA +100 mol % NaOH + 12.5 wt. % X-V-1 9.55 0.98 9.43 1.00 3.05 0.54 636A2NaVSA + 5 wt. % X-V-3 6.43 0.72 7.15 0.75 636A3 NaVSA + 10 wt. % X-V-37.93 0.77 6.70 0.76 7.07 0.77 636A4 NaVSA + 20 wt. % X-V-3 7.41 0.766.29 0.76 6.28 0.75 636B3 NaVSA + 10 wt. % X-V-3 9.52 0.81 6.49 0.747.03 0.77 636B4 NaVSA + 20 wt. % X-V-3 7.76 0.79 6.10 0.77 6.53 0.78639A FAA + 10 wt. % X-V-1 9.72 0.92 8.75 0.84 3.20 0.41 639A FAA + 10wt. % X-V-1 10.38 0.90 9.45 0.85 1.92 0.22 639B FAA + 50 mol % NaOH +12.5 wt. % X-V-1 8.97 0.92 8.85 0.85 639B FAA + 50 mol % NaOH + 12.5 wt.% X-V-1 9.46 0.95 8.68 0.83 1.73 0.17 639B FAA + 50 mol % NaOH + 12.5wt. % X-V-1 8.447 0.87 8.192 0.834 616B3 NaVSA + 20 wt. % X-V-1 5.870.71 6.14 0.72 6.57 0.78 100851A2 purified NaVSA + 5 wt. % X-V-1 5.920.67 6.68 0.70 5.58 0.69 100851A2 purified NaVSA + 5 wt. % X-V-1 7.420.79 7.08 0.74 5.99 100851A2 purified NaVSA + 5 wt. % X-V-1 6.57 0.776.45 0.71 5.87 0.74 100851A3 purified NaVSA + 10 wt. % X-V-1 6.27 0.076.84 0.72 6.17 0.72 100851A3 purified NaVSA + 10 wt. % X-V-1 6.97 0.757.50 0.74 6.78 0.77 100851A4 purified NaVSA + 20 wt. % X-V-1 5.84 0.716.53 0.73 5.21 0.70 100851A4 purified NaVSA + 20 wt. % X-V-1 6.28 0.816.28 0.75 100851A4 purified NaVSA + 20 wt. % X-V-1 6.22 0.76 6.82 0.755.48 0.74 100851B1 purified NaVSA + 2.5 wt. % X-V-5 6.42 0.65 6.50 0.656.09 0.65 100851B2 purified NaVSA + 5 wt. % X-V-5 5.76 0.62 6.72 0.646.27 0.65 100851B2 purified NaVSA + 5 wt. % X-V-5 6.77 0.73 7.27 0.676.48 0.71 100851B3 purified NaVSA + 10 wt. % X-V-5 5.83 0.61 7.07 0.645.57 0.60 100851B3 purified NaVSA + 10 wt. % X-V-5 6.66 0.80 7.27 0.696.05 0.68 100851B4 purified NaVSA + 20 wt. % X-V-5 6.50 0.65 6.25 0.615.22 0.59 100851B4 purified NaVSA + 20 wt. % X-V-5 5.50 0.66 6.59 0.665.82 0.66 100851C2 purified NaVSA + 5 wt. % X-V-1 6.52 0.70 6.40 0.685.52 0.67 100851C2 purified NaVSA + 5 wt. % X-V-1 7.23 0.78 7.03 0.75100851C3 purified NaVSA + 10 wt. % X-V-1 6.77 0.72 7.02 0.72 5.90 0.71100851C4 purified NaVSA + 20 wt. % X-V-1 6.05 0.72 6.08 0.71 4.66 0.68100851C4 purified NaVSA + 20 wt. % X-V-1 6.51 0.78 8.07 0.80 100851D1purified NaVSA + 2.5 wt. % X-V-5 7.07 0.74 7.28 0.71 5.87 0.69 100851D1purified NaVSA + 2.5 wt. % X-V-5 7.65 0.73 7.40 0.72 100851D2 purifiedNaVSA + 5 wt. % X-V-5 6.83 0.66 7.17 0.71 5.42 0.64 100851D2 purifiedNaVSA + 5 wt. % X-V-5 7.91 0.75 7.37 0.70 100851D3 purified NaVSA + 10wt. % X-V-5 6.70 0.67 6.87 0.66 5.21 0.64 100851D4 purified NaVSA + 20wt. % X-V-5 6.24 0.67 6.46 0.67 6.63 0.58 100851D4 purified NaVSA + 20wt. % X-V-5 7.01 0.68 6.61 0.70 100982A1 FAA + 10 wt. % X-V-1 9.66 0.899.02 0.86 3.40 0.50 100982A1 FAA + 10 wt. % X-V-1 8.47 0.86 100982A2 90wt. % FAA + 10 wt. % acrylic acid + 10 9.81 0.92 8.49 0.86 2.98 0.52 wt.% X-V-1 100982A2 90 wt. % FAA + 10 wt. % acrylic acid + 10 8.00 0.86 wt.% X-V-1 100982A3 80 wt. % FAA + 20 wt. % acrylic acid + 10 10.00 0.957.97 0.86 2.89 0.56 wt. % X-V-1 100982A3 80 wt. % FAA + 20 wt. % acrylicacid + 10 7.74 0.87 wt. % X-V-1 100982A4 70 wt. % FAA + 30 wt. % acrylicacid + 10 9.92 0.97 8.52 0.85 2.42 0.54 wt. % X-V-1 100982A4 70 wt. %FAA + 30 wt. % acrylic acid + 10 7.49 0.88 wt. % X-V-1 100982A5 60 wt. %FAA + 40 wt. % acrylic acid + 10 10.00 1.00 7.48 0.86 2.01 0.53 wt. %X-V-1 100982A5 60 wt. % FAA + 40 wt. % acrylic acid + 10 7.10 0.89 wt. %X-V-1 100982A6 50 wt. % FAA + 50 wt. % acrylic acid + 10 10.41 1.03 7.560.87 2.11 0.61 wt. % X-V-1 100982A6 50 wt. % FAA + 50 wt. % acrylicacid + 10 7.11 0.90 wt. % X-V-1 101012A1 purified NaVSA + 2.5 wt. %X-V-2 101012A2 purified NaVSA + 5 wt. % X-V-2 7.50 0.74 7.70 0.74 6.490.74 101012A3 purified NaVSA + 10 wt. % X-V-2 7.04 0.74 7.31 0.74 6.270.74 101012A4 purified NaVSA + 20 wt. % X-V-2 6.52 0.75 6.88 0.75 6.010.76 101012B1 purified NaVSA + 2.5 wt. % X-V-4 101012B2 purified NaVSA +5 wt. % X-V-4 7.53 0.71 7.64 0.71 6.93 0.72 101012B3 purified NaVSA + 10wt. % X-V-4 6.88 0.70 7.19 0.71 6.24 0.70 101012B4 purified NaVSA + 20wt. % X-V-4 6.34 0.68 6.78 0.70 6.08 0.70 101012D1 purified NaVSA + 2.5wt. % X-V-7 7.02 0.73 6.68 0.73 4.86 0.67 101012D2 purified NaVSA + 5wt. % X-V-7 7.35 0.74 7.24 0.74 6.58 0.73 101012D3 purified NaVSA + 10wt. % X-V-7 7.17 0.74 7.30 0.74 6.64 0.75 101012D4 purified NaVSA + 20wt. % X-V-7 6.33 0.72 6.64 0.74 5.83 0.74 101028A1 purified NaVSA + 10wt. % X-V-1 6.47 0.76 5.69 0.75 5.47 0.77 101028A2 90 wt. % purifiedNaVSA + 10 wt. % 6.67 0.81 6.01 0.79 4.67 0.72 FAA + 10 wt. % X-V-1101028A3 80 wt. % purified NaVSA + 20 wt. % 7.17 0.82 6.50 0.80 4.250.68 FAA + 10 wt. % X-V-1 101028A4 70 wt. % purified NaVSA + 30 wt. %7.33 0.84 6.77 0.81 4.12 0.66 FAA + 10 wt. % X-V-1 101028A5 60 wt. %purified NaVSA + 40 wt. % 7.69 0.85 7.00 0.83 3.43 0.60 FAA + 10 wt. %X-V-1 101028A6 50 wt. % purified NaVSA + 50 wt. % 8.25 0.87 7.29 0.853.80 0.63 FAA + 10 wt. % X-V-1 101029A2 VPA + 5 wt. % X-V-1 101029A3VPA + 10 wt. % X-V-1 11.38 1.49 5.70 1.00 2.37 0.89 101029A4 VPA + 20wt. % X-V-1 10.15 1.66 4.90 1.03 2.27 0.88 101029B2 VPA + 50 mol %NaOH + 5 wt. % X-V-1 101029B3 VPA + 50 mol % NaOH + 10 wt. % X-V-1 10.971.50 5.27 0.98 2.63 0.91 101029B4 VPA + 50 mol % NaOH + 20 wt. % X-V-110.23 1.62 5.10 1.01 2.06 0.88 684A FAA + 5 wt. % X-V-1 10.7 0.91 10.300.84 nm nm 684B FAA + 5 wt. % X-V-1 9.80 0.83 9.70 0.82 nm nm Dowex50WX4-200 5.37 0.77 5.51 0.77 4.92 0.76 (average of 15 experiments)Dowex 50W 0.77 0.06 0.81 0.08 0.80 0.06 (Standard deviation of 15experiments) nm: not measured

These examples show that the polymers of the invention display highpotassium binding capacity at physiological pHs. In particular polymersprepared from 2-fluoroacrylic acid can bind up to two times morepotassium than sulfonated polystyrene resins Dowex.

Titration Curves of alpha-fluoroacrylate Copolymer with acrylic acidfrom Table 11

The protocol was as per Helfferich, F. “Ion Exchange” (1962)McGraw-Hill, New York).

-   -   1. Approximately 50 mg of polymer (acid-form) was measured into        15×100 mm glass test tubes.    -   2. The volume of 1M NaOH required to generate the required mEq        was calculated, and enough water was added to the tubes to keep        the ratio of solution volume to resin weight constant.    -   3. The required mEq of NaOH was added to the polymer from a 1M        NaOH stock.    -   4. The tubes were sealed and rotated for 4 days to allow to come        to equilibrium    -   5. The equilibrated pH was measured while continuing to mix.

The results are shown in FIG. 16. This example shows thatpolyalpha-fluoroacrylate has a lower pKa (equal to pH value athalf-neutralization) than a methacrylic containing ion-exchange resinsuch as Amberlite CG50. The pKa value for the FAA gel material (100982A1from Table 11) can be estimated from FIG. 16 at about 5.6 versus 8 forAmberlite CG50. The incorporation of acrylic acid tends to increase pKain proportion to the wt-% of acrylic acid in the FAA-Acrylic acidcopolymer. This indicates that an electro-withdrawing group such asfluorine in the alpha position to COOH decreases the pKa and increasesthe overall binding capacity within the typical physiological pH rangeof 5-7.

Example 3 Procedure for Predicting Binding of Cations in the Human GI

This procedure was used to model the conditions of use of a potassiumbinder drug and measure the binding characteristics of the polymer forpotassium (target solute) in the presence of other competing cations. Ameal mimic was prepared and artificially digested in the presence ofpepsin and pancreatic juice. The sequence of addition of enzymes and thepH profile were controlled so that the digestion process was simulateddown to the jejunum level. The test polymers, preloaded with lithium,were added to the digested meal mimic and allowed to equilibrate for afixed period of time; the mixture was then centrifuged and thesupernatant was assayed for Na⁺, K⁺, NH₄ ⁺, Ca²⁺, and Mg²⁺ by ionchromatography. The lithium released was computed as the total cationexchange, while the decrease in concentrations of the other cations wasused to compute their binding variations in western diets.

Preparation of Resin

Resin (test resin, or Dowex 50WX4-200 used as a comparative), was washedextensively in 1M HCl to convert it to the H-form. It was then washedextensively in 1M LiOH. Excess LiOH was removed by washing in ddH₂O. Theresins were lyophilized and stored in a desiccator.

FIG. 1 depicts starting cation concentrations in meal mimic and FIG. 2depicts binding of cations by resins in meal mimic.

Measurement of Binding Capacities in Cecal and Fecal Extracts

Two volumes (w/v) of ice-cold ddH₂O were added to the human feces and tonormal rabbit cecal contents. These were incubated with rotation at 4°C. with end-over-end rotation for at least 1 hour to extract solublecations. Fecal and cecal extracts, as well as thawed meal mimics, werecentrifuged at 2000 g for 10 minutes to clarify. Approximately 50 mgLi-form Dowex 50W was weighed into 16×100 mm glass test tubes. Controltest tubes were included that contained no resin. Clarified extracts ormimics were added to a final resin concentration of 2.5 mg/ml. 5-10 mlof extracts or mimic were added to the control test tubes. Tubes weresealed and rotated at 4° C. for 90 minutes. The tubes were centrifugedat 500 g for thirty minutes to precipitate the resin. Supernatantsamples were taken. The samples were then prepared for ionchromatography by spinning at 13,000 g for ten minutes, taking thesupernatant and rapidly passing across a 3000 Da cutoff dialysismembrane by centrifugation. Extracts were further diluted 1:5 (v/v) inddH₂O before applying to the IC columns. Start (without resin) andequilibrium (with resin) concentrations of Li⁺, Na⁺, K⁺, NH₄ ⁺, Ca⁺⁺ andMg⁺⁺ were determined, and the amount (in mmoles cation/gm resin) of Li⁺released, as well as Na⁺, K⁺, NH₄ ⁺, Ca⁺⁺ and Mg⁺⁺ bound werecalculated.

Procedure for Measuring the Binding of Cations by Resins in Human FecalExtracts

Resins and feces were prepared as follows. Resins were washedextensively in 1M HCl to convert them to the H-form. Excess HCl wasremoved by washing in ddH₂O. The resins were lyophilized and stored in adesiccator. Fecal samples were obtained from two human subjects, frozenimmediately and stored at −80° C. to minimize ammonium production exvivo.

All experiments were performed in triplicate. Error bars on FIGS. 3 and4 indicate standard deviations values. Fecal samples were resuspended intwo volumes of ice-cold ddH₂O (w/v) and incubated overnight at 4° C. toextract soluble cations. The extract was then clarified by centrifugingat 2000 g for ten minutes. H-form resins were weighed into disposable 15ml-capacity columns. They were them washed extensively in 150 mM LiOH toconvert them to the Li-form. They were washed in ddH₂O to remove excessLiOH. Clarified fecal extract was applied to the columns to a finalresin concentration of 2.5 mg/ml of extract. A sample was retained forcalculating resin concentrations in the absence of resin. Columns werecapped and rotated at 4° C. for three hours. They were then eluted bycentrifugation into 50 ml polypropylene tubes. The pH of eluted extractsand retained clarified fecal extracts were measured (it had not changed:Sample 1 pH was 6.75, sample 2 pH was 7.1). The samples were thenprepared for ion chromatography by spinning at 13,000 g for ten minutes,taking the supernatant and rapidly passing across a 3000 Da cutoffdialysis membrane by centrifugation. Extracts were further diluted 1:5(v/v) in ddH₂O before applying to the IC columns. Start (without resin)and equilibrium (with resin) concentrations of Li⁺, Na⁺, K⁺, NH₄ ⁺, Ca⁺⁺and Mg⁺⁺ were determined, and the amount (in mmoles cation/gm resin) ofLi⁺ released, as well as Na⁺, K⁺, NH₄ ⁺, Ca⁺⁺ and Mg⁺⁺ bound werecalculated. In FIG. 4 “Total occupied” refers to the sum of Li⁺ (i.e.monovalent) binding sites occupied by the other cations, taking intoaccount the divalent nature of Ca⁺⁺ and Mg⁺⁺.

Data presented in FIG. 4 demonstrate that the ex-vivo binding ofpotassium in human fecal extracts for the FAA based material is abouttwice as much that of Dowex 50WX4-200 (a material essentially identicalin composition to the potassium binder Kayexalate). The ex-vivo bindingof potassium by the Dowex resin is essentially the same as that reportedfor polystyrene sulfonate resins in human clinical studies, whichestablishes this method as a good predictor for in-vivo bindingperformance. It also indicates that other cations, in particularMagnesium and Calcium, compete with potassium for the binding sites ofthe polymers. FIG. 3 depicts the original concentrations of cations inthe Feces of Subject 1 and Subject 2. FIG. 4 depicts the binding ofcations in human fecal extracts to cation exchange resins.

Example 4 Method of Selection of Semi-Permeable Membrane with HighPotassium Binding Selectivity over Magnesium and Calcium

This protocol describes a method to optimize polymeric materials withregards to their ion permselectivity characteristics, which then can beused as the shell component for the making of potassium selectivecore-shell ion-exchange particles.

Polymer Synthesis and Membrane Preparation:

Polymeric membrane materials with different compositions were preparedby radical copolymerization of DBA (N,N′-dibutyl acrylamide) and DEAEMA(N,N′-diethylaminoethylmethacrylate) in a glove box using miniaturizedreactors in a library format. AIBN was used as the initiator and ethanolas the solvent. Polymers were isolated by precipitation into water,freeze-dried, and characterized by GPC and H-NMR. The composition of thepolymer (DBA mol %) ranges from 30% to 70% and molecular weight rangesfrom 200K to 300K as shown below:

TABLE 14 Polymer ID 101224 D1 D2 D3 D4 D5 D6 Mn (×10³) 327 326 322 285240 217 Mw(×10³) 584 563 520 467 411 340 PDI 1.78 1.73 1.61 1.64 1.711.56 Composition 31.2 37.1 48.5 56.1 64.4 68.5 (DBA, mol %)

Polymer membranes were prepared by casting a 2-wt % toluene solution ofDBA-co-DEAEMA onto a regenerated cellulose dialysis membrane (RCmembrane with MWCO of 14 K). After toluene was evaporated, a polymermembrane was formed on the top of dialysis membrane. A compositemembrane of polymer membrane and RC membrane was thus prepared.

Permeability Study on Cations

The composite membrane was first clamped onto a glass tube with diameterof 13 mm, and then immersed into a 2 L of donor solution of cations. Thetube was filled with 10 ml of acceptor solution (lactose solution withthe same osmolality as the donor solution (240 mM)). The acceptorsolution was sampled at a specified time interval and analyzed by ionchromatography. See FIG. 5.

Donor solution was prepared by mixing the aqueous solution of NaCl, KCl,CaCl₂.2H₂O, and MgSO₄.7H₂O. The solution was buffered to pH 6 by using14 mM of MES (2-[[N-morpholine]ethanesulfonic acid] solution. Theconcentrations of different cations determined by IC were as follows:[Na⁺], 40.46 mM; [K⁺], 31.44 mM; [Mg²⁺], 33.25 mM; [Ca²⁺], 22.324 mM.

Determination of the permeability coefficient (P) of different cations:As mentioned in the measurement set-up, the acceptor solution wassampled at a specific time interval and analyzed by IC. Assuming aFick's first law of diffusion, P is readily obtained by linearization ofthe data, following a method of calculation reported in equation 1 in G.Van den Mooter, C. Samyn, and R. Kinget, International Journal ofPharmaceutics, 111, 127-136(1994). The permeability coefficients ofdifferent cations were thus calculated from the slope from this linearrelationship.

$\begin{matrix}{{- {\ln\left( \frac{C_{o} - C_{a}}{C_{o}} \right)}} = {\frac{PS}{Va}t}} & {{Equation}\mspace{20mu} 1}\end{matrix}$Where C_(o) is the initial concentration of the solute in the donorcompartment and C_(a) the concentration in the acceptor compartment attime t, Va is the volume of the acceptor compartment, and S the surfaceof the membrane.

Permselectivity: As described above, the permeability coefficient wascalculated for each cation. By normalizing the permeability coefficientof Na⁺ as 1, the permselectivity for cations M1 and M2 can be calculatedas follows: P_(M1) ^(M2)=P(M2)/P(M1)

Permeability Coefficients of Different Cations through DifferentMembranes:

Table 14 shows the permeability coefficients of different cations atdifferent membranes. When polymers are more hydrophilic (Polymer D3 andD4 with DBA % 48.5 and 56.1%, respectively), all cations, such as Na⁺,K⁺, Mg²⁺, and Ca²⁺, are more permeable and their permeabilitycoefficients are comparable to those through a blank dialysis membrane(RC membrane) and reflect the self-diffusivity of the cations. However,with the increasing DBA content in polymer membrane (See Table 15 for D5and D6), the permeability coefficients of different cations decreased ascompared with blank membrane, which means that the hydrophobic nature ofpolymer membrane could make cations less permeable through thehydrophobic barrier.

TABLE 15 Permeability coefficients of cations at different membranes DBAPMg²⁺ PCa²⁺ Polymer ID (mol %) PNa⁺(cm/sec) PK⁺(cm/sec) (cm/sec)(cm/sec) D3 48.5 2.41(±0.26)E−4 3.11(±0.34)E−4 6.50(±0.08)E−5 6.0(±0.07)E−5 D4 56.1 4.28(±0.44)E−5 6.11(±0.61)E−4 1.13(±0.11)E−51.04(±0.05)E−5 D5 64.4 4.32(±0.20)E−6 5.79(±3.59)E−6 5.42(±4.11)E−73.32(±3.33)E−7 D6 68.5 1.50(±0.05)E−7 — — —

Another characteristic for the permeability of different cations istheir permselectivity. By normalizing the value of P_(Na+) as 1, thepermselectivity for other cations can be calculated the results areshown in Table 16. The permselectivity of P_(Mg)/P_(Na) andP_(Ca)/P_(Na) decreases with the increasing DBA content in polymermembranes, which implies that more hydrophobic polymer membranes mayhave better selectivity for different cations. For a better selectivityfor different cations, two factors should be considered—the chargedensity and the membrane hydrophobicity.

TABLE 16 Polymer ID DBA (%) P(K⁺)/P(Na⁺) P(Ca²⁺)/P(Na⁺) P(Mg²⁺)/P(Na⁺)P(K⁺)/P(Mg²⁺) D3 48.5 1.29 0.27 0.25 5.16 D4 56.1 1.43 0.26 0.24 5.96 D564.4 1.34 0.13 0.08 16.75

Example 5 Synthesis of poly-2-fluoroacrylic Acid Beads

Beads are prepared by a direct suspension process where a mixture of2-fluoroacrylic methyl ester/divinylbenzene/benzoyl peroxide in a weightratio 90/9/1 are dispersed in water under high shear withpolyvinylalcohol as a suspending agent. The suspension is stirred andheated at 80° C. for 10 hours. The residual monomer is eliminated bysteam stripping. The beads are then filtered and treated with aqueous 3MNaOH to hydrolyze the polymer, then washed, treated with HCL,water-washed, and finally dried to form the desired polyα-fluoroacrylicacid particles. The average bead diameter is 250 microns as measured byMaster Sizer (Malvern UK).

Example 6 Preparation of Poly-2-fluoroacrylicAcid/Core-(DBA-DEAEMA)/Shell Particles

The core-shell particles are prepared by forming a coating of polymer D2on the poly-2-fluoroacrylic acid beads prepared in example 5 using aWurster coater. The shell polymer prepared in example 4 is firstdissolved at 20 wt-% in toluene, and the thus obtained solution thendispersed in water in a 1:4 weight ratio with 2 wt-% based on theorganic phase of CTAB (Hexadecyltrimethyl-Ammonium Bromide) as asurfactant, using a Ultra-Turrax high-shear homogeneizer. The toluene isthen driven off by evaporation under reduced pressure. The averagediameter of the dispersion particles is 0.3 micrometer, as measured byDynamic Light Scattering. The poly-2-fluoroacrylic acid beads arespray-coated with the shell polymer dispersion using a Wurster fluid bedcoater 2″-4″/6″ Portable Unit. The fluidized bed unit is operated sothat an average 5 microns thick coating is deposited on the coreparticles.

The potassium binding capacity when measured in a fecal extract asdescribed in Example 3 is expected to be twice higher than that measuredwith the uncoated poly-α-fluoroacrylic acid beads.

Example 7 Preparation of Polystyrene Sulfonate/Core-polyethyleneimineShell Particles with Na+ and K+ Selective-Binding Propertie

Procedure for Coating PEI on Dowex Beads

PEI (poly(ethyleneimine), Mw10,000) and Dowex beads (H-form, X4-200)were purchased from commercial sources. PEI aqueous solutions withdifferent concentrations were prepared by dissolving PEI directly intonanopure water.

Weighed dried Dowex beads were mixed with PEI aqueous solution inlibrary format glass tubes. After a specified reaction time, the tubeswere sealed and centrifuged at 1000 rpm for 15 minutes, the supernatantsolutions were then decanted off. To the beads in each tube was addednanopure water to a total volume of 10 ml and all tubes were sealed andtumbled for 30 minutes. The same tumbling-centrifuging was repeated 3times. The beads were freeze-dried and weighted until a constant weightwas obtained.

The reaction solution composition and gel weight increase are displayedin Table 17.

TABLE 17 Conditions for coating PEI on Dowex beads Dowex Bead PEI Conc.PEI Reaction Weight increase Weight (gm) (wt %) volume (ml) time (hours)Coated bead ID (Δwt %) 0.1274 2.5 10 1 DOWEX(2.5 wt-1 h) * 0.2223 2.5 106 DOWEX(2.5 wt-6 h) 3.1 0.1609 1.5 10 1 DOWEX(2.5 wt-1 h) * 0.2407 1.510 6 DOWEX(2.5 wt-6 h) 0.9 0.2016 0.5 10 1 DOWEX(2.5 wt-1 h) * 0.23470.5 10 6 DOWEX(2.5 wt-6 h) * * No weight increase was observed.Method for Binding Study

A mixture of NaCl, KCl, MgCl₂, and CaCl₂ was dissolved in a MES buffer(pH6.0) (MES, 2-[N-morpholine]ethanesulfonic acid]. The concentrationfor each cation was determined by IC. The concentrations for Na⁺, K⁺,Mg²⁺, and Ca²⁺ are 26.4 mM, 9.75 mM, 4.75 mM and 4.16 mM respectively.

Weighed dried PEI-coated bead was put into a tube which contains 5-ml ofMES buffer solution of NaCl, KCl, MgCl₂, and CaCl₂. The tube was sealedand tumbled. After a certain period of time as indicated in FIG. 6, thetube was centrifuged. 100 microliter of solution was then taken out fromthe supernatant for IC analysis. The binding amount of PEI coated beadsfor different cations were calculated from the concentration change inthe solution. The calculation is as follows:Ion bound in beads (mmol/g)=[V×(C ₀ −C _(t))/{[weight of beads]×1000}

-   C₀: initial concentration of metal ion (in mM)-   C_(t): concentration of metal ion after bead binding at a certain    time (t hrs) (in mM)-   V: solution volume (5 ml)-   Weight of beads (gm)

The binding data of different PEI coated beads for different cations areshown in FIG. 6. PEI coated Dowex beads show higher Na⁺ and K⁺ bindingthan the uncoated beads (bare beads). The coated beads show much moreselective binding than bare beads. The thicker the PEI coating (e.g.Dowex (2.5 wt-6 h), coated from 2.5 wt % PEI solution for 6 hours), themore selective for the different cations. The binding kinetic studyshows that the binding of cations equilibrates faster for the thinnercoated beads and bare beads.

Example 8 Polystyrene Sulfonate Beads with Eudragit Shell

Shell material: Eudragit RL100 (Rohm), a copolymer of acrylic andmethacrylic acid esters with 8.85-11.96% cationic ammonio methacrylateunits, 10 wt % in ethanol and 10 wt % triacetin. Core: Lewatit(cross-linked polystyrene sulfonate in sodium form), size—300 μm.

The shell was applied using a FluidAir Wurster coater.

Binding was measured under following conditions:

-   -   Donor solution: 50 mM KCl and 50 mM MgCl₂    -   Bead concentration: 4 mg/ml    -   Duration: 6 hours

FIG. 7 shows the effect of the shell on Mg²⁺ and K⁺ binding. Withincreasing ratio of shell to core, Mg²⁺ binding decreased and K⁺ bindingincreased. 20 wt % shell coating gave a K⁺ binding capacity of 1.65meq/gm, which is about 3 times higher than for uncoated Dowex.

Example 9 Polystyrene Sulfonate Beads with Benzylated Polyethylene ImineShell

Synthesis of Benzylated Polyethyleneimine (PEI)

To a 250 ml of round bottom flask were charged 15.6 g of PEI (363 mmolof —NH₂) and 125 ml of ethanol, this mixture was magnetically stirreduntil PEI was completely dissolved, then 30 g of NaHCO₃ (FW, 84; 256mmol) and 40 ml of benzyl chloride (363 mmol) were subsequently added.The above mixture was reacted at 55° C. under nitrogen atmosphereovernight. Dichloromomethane was added to the slurry reaction mixture,followed by filtration to remove inorganic salt. The solvent in filtratewas removed by vacuum. Dicholromethane was used again to re-dissolve thereaction product; inorganic salt was further removed by filtration. Thesolvent in the filtrate was removed again under vacuum. Finally, theproduct was triturated in hexane, filtered and washed with hexane, anddried under vacuum. The benzylation degree was 84% as determined by¹HNMR. Similar materials with various degree of benzylation(respectively 20% and 40% for Ben(20) and Ben(40)) were prepared byadjusting the benzyl chloride to PEI ratio.

Benzylated polyethylene imine (Ben-PEI) was coated onto Dowex beads.

The shell was coated using solvent coacervation. The shell Ben(84)-PEIwas dissolved in methanol and water mixture (3:1) at pH of 3. Shell andcore were mixed for 5 minutes and methanol was removed by rotovap (40minutes), isolated, washed, and dried.

Binding was measured under following conditions:

-   -   Donor solutions: 50 mM KCl and 50 mM MgCl₂    -   Bead concentration: 4 mg/ml    -   Duration: 6 and 24 hours

Results of the binding measurements are shown in FIG. 8. Ben(84)-PEIshowed selective binding for potassium after 6 and 24 hours as revealedby lower Mg²⁺ binding compared to naked beads.

FIG. 9 depicts the stability of Ben(84)-PEI coated Dowex (K) beads underacid conditions representative of the acidic conditions in the stomach.The beads were exposed to pH 2 HCl for 6 hours, isolated, and dried.Binding selectivity was tested for the post-treated beads. Bindingconditions were as follows:

-   -   Donor solutions: 50 mM KCl and 50 mM MgCl₂    -   Bead concentration: 4 mg/ml    -   Duration: 6 and 24 hours        The coating was stable and binding selectivity was maintained at        6 and 24 hours.

Example 10 FAA beads with Benzylated Polyethylene Imine Shell

The shell was applied on the FAA core by the process of solventcoacervation. The shell, Ben(84)-PEI, was dissolved in methanol andwater mixture (3:1) at pH of 4.5. The shell and core were mixed for 5minutes and methanol was removed by rotovap (40 minutes), isolated,washed, and dried.

Binding was measured under following conditions:

-   -   Donor solutions: 50 mM KCl and 50 mM MgCl₂    -   Bead concentration: 4 mg/ml    -   Duration: 6 hours

The potassium binding was calculated from actual magnesium uptake andoverall binding capacity of polymer which was 5.74 meq/gm. The resultsare shown in FIG. 10. Increasing the ratio of shell/core caused adecrease in magnesium binding which indicates an increase in potassiumbinding.

Example 11 Coating by Controlled Precipitation Induced by pH Change

The shell comprised of Benzylated PEI, Ben (˜20%); and Ben (˜40%) on aDowex(K) core. Binding was measured in 50 mM KCl and 50 mM MgCl₂.

FIG. 11 shows the results of the binding experiments. Controlledprecipitation method for 40% benzylated PEI shows better coating andthis combination of coating method and materials gives higher bindingselectivity.

Example 12 Membrane Screening of Shell Polymers

Shell polymers were screened by coating a flat membrane via solventcasting and using the coated membrane as the barrier in a diffusioncell, as depicted in FIG. 15. Donor solution was 50 mM2-[N-morpholino]ethane sulfonic acid (MES) buffer at pH6.5 with 50 mM K⁺and Mg²⁺. Permeability coefficient was calculated as described inExample 4 above. Cross-linked B-PEI was tested using this method. B-PEI(35 mol %) was cross-linked with 1,4-butanediol diacrylate. Thecross-linker was reacted on the top of dried B-PEI for 4 hours. Thescreening was performed in 50 mM KCl and 50 mM MgCl2 in 50 mM MESbuffer. Cross-linker (diacrylate) reacted with B-PEI (35 mol %)membrane. As shown in FIG. 13, addition of the cross-linker reducedpermeability coefficient and also showed good selectivity.

Blends of Eudragit RL 100 and RS 100 were also evaluated using themethod of FIG. 12. The results are shown in FIG. 14. Adding RS100 intoRL100 can reduce the permeability and the permselectivity stays in thesame range. Membranes with more than 50 wt % of RS 100 lost selectivity([K⁺] in the same scale, but [Mg²+] much higher than other composites).

Example 13 Effects of Bile Acids on K⁺ Binding

Dowex(Li) (˜100 μm) was first coated with PEI aqueous solution. Thesupernatant was removed and the coat was further crosslinked with1,2-Bis-(2-iodoethoxy)-ethane (BIEE). Binding was measured in 50 mM KCland 50 mM of MgCl2, MES buffer, pH 6.5. Bile acids extract used was 2mg/ml (bile extract porcine with 60% bile acids and 40% unknowns, i.e.,free fatty acids, phospholipids, etc.). Time: 6 and 24 hrs and Beadcontent: 4 mg/ml. Results are shown in FIGS. 15A and 15B. Enhancedperformance of the shell was observed in the presence of bile acids,fatty acids, and lipids.

Example 13 Synthesis of methyl 2-fluoroacrylate Beads

All chemicals were purchased from commercial sources and used asreceived, except as noted. Reactions were carried out under nitrogen.The monomers used were methyl 2-fluoroacrylate (MeFA); crosslinkers weredivinylbenzene (DVB); initiator: azobisisobutyronitrile (AIBN) andlauroyl peroxide (LPO); suspension stabilizer polyvinylalcohol (PVA)—MW85,000-146,000, 87-89% hydrolyzed; and salt: sodium chloride (NaCl).MeFA and DVB were vacuum distilled.

General Procedure for Synthesis of MeFA Beads:

To a 3-neck Morton-type flask equipped with a mechanical stirrer, awater condenser and a rubber septum were charged with an aqueoussolution containing PVA (and NaCl in some cases). The solution wasstirred and purged with nitrogen for 20 min. An organic solutioncontaining MeFA, DVB and an initiator was added. The mixture was stirredat room temperature for 20 min, and heated in a 70-80° C. oil bath for2-6 hrs. The reaction mixture was cooled down to room temperature andthe white solid was washed with water. The solid was examined bymicroscope and/or Malvern Master Sizer. The solid was either isolated byfreeze-drying or used directly in the next step (hydrolysis reaction).

General Procedure for Hydrolysis of MeFA Beads to Produce FAA Beads:

MeFA beads were suspended in 10 wt % NaOH (or KOH) aqueous solution at aconcentration of 10 wt %. The mixture was heated in a 90° C. oil bathfor 20 hrs, and then allowed to cool down to room temperature. Solid waswashed with water and 4M HCl and then freeze-dried.

Synthesis of MeFA Beads with no NaCl in Aqueous Phase and AIBN asInitiator:

To a 250 mL 3-neck Morton-type flask equipped with a mechanical stirrer,a water condenser and a rubber septum were charged 75 gm aqueoussolution containing 1 wt % PVA. The solution was stirred at 605 rpm andpurged with nitrogen for 20 min. An organic solution containing MeFA(13.5 g), DVB (1.5 g) and AIBN (0.075 g) was added. The mixture wasstirred at room temperature for 20 min and heated in a 70° C. oil bathfor 6 hrs. The reaction mixture was cooled down to room temperature, andthe white solid was washed with water. Large irregular particles (˜1 mm)were observed under microscope

Synthesis of MeFA Beads with NaCl in Aqueous Phase and AIBN asInitiator:

To a 250 mL 3-neck Morton-type flask equipped with a mechanical stirrer,a water condenser and a rubber septum were charged 75 g aqueous solutioncontaining 2 wt % PVA and 3.75 wt % NaCl. The solution was stirred at502 rpm and purged with nitrogen for 20 min. An organic solutioncontaining MeFA (13.5 g), DVB (1.5 g) and AIBN (0.075 g) was added. Themixture was stirred at room temperature for 20 min, and heated in a 70°C. oil bath for 6 hrs. The reaction mixture was cooled down to roomtemperature and the white solid was washed with water. Spherical beads(˜90 μm) and some large gel particles were observed under microscope

Synthesis of MeFA Beads with no NaCl in Aqueous Phase and LPO asInitiator:

To a 250 mL 3-neck Morton-type flask equipped with a mechanical stirrer,a water condenser and a rubber septum were charged 75 g aqueous solutioncontaining 2 wt % PVA. The solution was stirred at 503 rpm and purgedwith nitrogen for 20 min. An organic solution containing MeFA (13.5 g),DVB (1.5 g) and LPO (0.15 g) was added. The mixture was stirred at roomtemperature for 20 min and heated in a 70° C. oil bath for 2 hrs. Thereaction mixture was cooled down to room temperature, and solid waswashed with water, and freeze-dried. A white powder (11.85 g) wasobtained. Large irregular particles (0.5-1 mm) of aggregated beads wereobserved under microscope.

Synthesis of MeFA Beads with NaCl in Aqueous Phase and LPO as Initiator:

To a 100 mL 3-neck Morton-type flask equipped with a mechanical stirrer,a water condenser and a rubber septum were charged 300 g aqueoussolution containing 1 wt % PVA and 3.75 wt % NaCl. The solution wasstirred at 307 rpm and purged with nitrogen for 20 min. An organicsolution containing MeFA (54 g), DVB (6 g) and LPO (0.6 g) was added.The mixture was stirred at room temperature for 20 min and heated in a70° C. oil bath for 4 hrs. The reaction mixture was cooled down to roomtemperature, solid was washed with water, and freeze-dried. A whitepowder (56 g) was obtained. Spherical beads (˜100 μm) were observedunder microscope.

Example 14 In vivo Efficacy of fluoroacrylate (FAA) Polymer-NH₄ FormCompared to Kayexalate (Polystyrene Sulfonate)

40 male rats were acclimated for three days on Harlan Teklad DietTD.04498, whereupon they were randomly assigned to four groups of tenrats. The four groups were then fed for a further four days an admixtureof Harlan Teklad Diet TD.04498 with test or control articles accordingto Table 18.

TABLE 18 Test Article Concen- Dose Number tration in levels of Diet (%diet Group Animals Treatment Groups (g/kg) w/w) 1 10 Cellulose Control20   2% 2 10 Kayexalate: NH₄ ⁺-form 21.5 2.15% 3 10 FAA polymer: NH₄⁺-form 23  2.3% 4 10 FAA polymer: NH₄ ⁺-form 11.5 1.15%

2.15% Kayexalate: NH₄ ⁺-form corresponds to 2% Kayexalate: H⁺-form and2.3% FAA polymer:NH₄ ⁺-form corresponds to 2% FAA polymer:H⁺-form. Thebinding capacity values reported below correspond to the H⁺-formpolymers. The FAA-polymer used in this in vivo study was synthesizedusing the same procedure as shown in Table 11, for polymer number100982A1, and the material was further ion exchanged with ammonium ions.

Feces were collected from each rat and pooled each 24 hrs. Feces werelyophilized and dry weights per rat per day were recorded. Fecal cationswere extracted in 1M HCl overnight and measured using IonChromatography. The total moles of each cation (Sodium, Ammonium,Potassium, Magnesium and Calcium) excreted into the feces of each ratper day was calculated.

It was determined that the effect of the polymers on fecal cationsreached equilibrium after two days of treatment. The data for the thirdand fourth days were pooled and are shown in FIG. 17. A statisticalanalysis of the data from the third and fourth days of treatmentindicates that FAA polymer:NH₄ ⁺-form binds significantly more Sodium,Ammonium, Potassium and Calcium than does Kayexalate.

The amount of each cation (in mEq) bound per gram of H⁺-form polymer wascalculated based on the dietary intake of polymer and the differencebetween the amount of cation in the feces of control animals versus theamount of cation in the feces of test animals on diets containing 2%test articles. The calculated in vivo binding capacities for Kayexalateand FAA polymer:NH₄ ⁺-form are shown in Table 19.

TABLE 19 mEq cations bound in vivo per g resin (when present at 2% indiet) Na NH₄ K Mg Ca Total mEq Kayexalate 1.09 0.41 0.24 0.66 0.46 2.87FAA polymer:NH₄ ⁺-form 2.11 1.10 0.44 1.13 1.30 6.07

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

1. A method for removing potassium from the gastrointestinal tract of amammal in need thereof, the method comprising orally administering apharmaceutical composition to the mammal, the pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and apotassium-binding polymer or a salt thereof, the potassium-bindingpolymer being a crossliniked α-fluoroacrylic acid polymer, acrossliniked difluoromaleic acid polymer, or a salt thereof wherein saidpotassium removal is derived from repeat units selected from the groupconsisting of α-fluoroacrylic acid, difluoromaleic acid, vinylsulfonicacid, acrylic acid, vinyl phosphonate, vinyl-1,1-bisphosphonate, vinylsulfonate, vinyl-1,2-disulfonate, itaconic acid, vinyl sulfamate,styrene sulfonate, α-hydroxyacrylic acid, a salt thereof, and acombination thereof in the crosslinked α-fluoroacrylic acid polymer,crosslinked difluoromaleic acid polymer, or salt thereof, whereby thepharmaceutical composition passes through the gastrointestinal tract ofthe mammal, and removes a therapeutically effective amount of potassiumion from the gastrointestinal tract of the mammal.
 2. The method ofclaim 1 wherein the mammal is a human.
 3. The method of claim 1 whereinthe potassium-binding polymer is an alpha-fluoroacrylic acid polymercrossliniked with divinylbenzene, ethylene bisacrylamide,N,N′-bis(vinylsulfonylacetyl) ethylene diamine, 1,3-bis(vinylsulfonyl)2-propanol, vinylsulfone, N,N′-methylenebisacrylamide polyvinyl ether,polyallylether, or a combination thereof.
 4. The method of claim 1wherein the potassium-binding polymer is an alpha-fluoroacrylic acidpolymer crossliniked with divinyl benzene.
 5. The method of claim 1wherein the salt of the α-fluoroacrylic acid group is selected fromCa²⁺, H⁺, NH₄ ⁺, Na⁺, or a combination thereof.
 6. The method of claim 1wherein said potassium-binding polymer has an in vitro potassium bindingcapacity of equal to or more than 6 mmol per gram of polymer at a pH ofabout 5.5.
 7. The method of claim 1 wherein the in vivo potassiumbinding capacity is 1.5 mmol or more per gram of said polymer.
 8. Themethod of claim 1 wherein the in vivo potassium binding capacity is 2mmol or more per gram of said polymer.
 9. The method of claim 1 whereinthe in vivo potassium binding capacity is 4 mmol or more per gram ofsaid polymer.
 10. The method of claim 7 wherein the potassium bindingcapacity is calculated by measuring the amount of potassium in the fecesafter administration of the potassium binding polymer to a humanpatient.
 11. The method of claim 1 wherein the pharmaceuticalcomposition is administered in the form of a chewable tablet.
 12. Themethod of claim 1 wherein the potassium-binding polymer is non-absorbed.13. The method of claim 1 wherein the potassium-binding polymer isadministered in a dose of about 10 grams/day to about 20 grams/day. 14.The method of claim 2 wherein the human is being treated with an agentthat causes potassium retention, the agent causing potassium retentioncomprising an angiotensin-converting enzyme inhibitor or an angiotensinreceptor blocker.
 15. The method of claim 14 wherein thepotassium-binding polymer and the agent that causes potassium retentionare administered simultaneously.
 16. The method of claim 14 wherein thepotassium-binding polymer and the agent that causes potassium retentionare administered a few minutes apart, a few hours apart, or a few daysapart.
 17. A method for removing potassium from the gastrointestinaltract of a mammal in need thereof, the method comprising orallyadministering a pharmaceutical composition to the mammal, thepharmaceutical composition comprising a pharmaceutically acceptableexcipient and a potassium-binding polymer, the potassium-binding polymerbeing a crossliniked alpha-fluoroacrylic acid polymer comprising acationic counterion of Ca²⁺wherein said potassium removal is derivedfrom repeat units selected from the group consisting of α-fluoroacrylicacid, difluoromaleic acid, vinylsulfonic acid, acrylic acid, vinylphosphonate, vinyl-1,1-bisphosphonate, vinyl sulfonate,vinyl-1,2-disulfonate, itaconic acid, vinyl sulfamate, styrenesulfonate, α-hydroxyacrylic acid, a salt thereof, and a combinationthereof in the crosslinked α-fluoroacrylic acid polymer, whereby thepharmaceutical composition passes through the gastrointestinal tract ofthe mammal, and removes a therapeutically effective amount of potassiumion from the gastrointestinal tract of the mammal.
 18. The method ofclaim 17 wherein the alpha-fluoroacrylic acid polymer is crosslinikedwith divinylbenzene, ethylene bisacrylamide,N,N′-bis(vinylsulfonylacetyl) ethylene diamine, 1,3-bis(vinylsulfonyl)2-propanol, vinylsulfone, N,N′-methylenebisacrylamide polyvinyl ether,polyallylether, or a combination thereof.
 19. The method of claim 17wherein the potassium-binding polymer is in a bead form.